Theranostic Applications of Nanotechnology in Neurological Disorders 9789819995103, 9819995108

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Akash Gautam Vishal Chaudhary   Editors

Theranostic Applications of Nanotechnology in Neurological Disorders

Theranostic Applications of Nanotechnology in Neurological Disorders

Akash Gautam  •  Vishal Chaudhary Editors

Theranostic Applications of Nanotechnology in Neurological Disorders

Editors Akash Gautam Center for Neural and Cognitive Sciences University of Hyderabad Hyderabad, Telangana, India

Vishal Chaudhary Department of Physics University of Delhi New Delhi, Delhi, India

ISBN 978-981-99-9509-7    ISBN 978-981-99-9510-3 (eBook) https://doi.org/10.1007/978-981-99-9510-3 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Paper in this product is recyclable.

Foreword

The brain remains the most complex among all organs and consumes ~20% of the energy required by the body. The high energetic demands necessitate the consumption of large quantities of oxygen and nutrients, including glucose, into the neuronal bed, which, along with the pro-oxidant mitochondrial ETC constituent ubiquinone, make the brain particularly vulnerable to a host of pathologies, many of which are associated with mitochondrial dysfunction, neuronal inflammation, and imbalances in neurotransmitters. The increased global lifespan in humans, exposure to anthropogenic chemicals associated with the production and consumption of goods, coupled with the fact that age itself is the leading risk factor for neurodegenerative disorders, has led to an increased societal burden associated with the onset and progress of neurodegenerative and neurological disorders worldwide. Unlike chronic and infectious diseases, cancers and other autoimmune disorders, where rapid strides in diagnoses and treatments have been made primarily due to the ease of “access” to the pathology, there remains a significant gap in the successful resolution of neurodegenerative and neurological afflictions. Blood–brain, blood–spinal, and blood–nerve barriers have inhibited both diagnoses and treatment regimens, with many small-molecule candidates that have had experimental, in  vitro, and in  vivo success failing in subsequent clinical trials or shortly after approval. Furthermore, most approved drugs are mere palliatives as they only manage the symptoms of the disease, with cures elusive at the time of writing. A paradigm shift is essential. Theranostic Applications of Nanotechnology in Neurological Disorders includes a compendium of chapters that Prof. Gautam and Prof. Chaudhary have carefully curated to address emerging alternatives to the existing arsenal of medications available to address outcomes associated with neurodegenerative and neurological disorders. The book describes inroads made in theranostics through nanotechnological advances and breakthroughs in biomedicine, emphasizing the aforementioned disorders and syndromes. A phalanx of leading researchers in nanotechnology with specialization in neuronal applications discusses the latest tools in the field, such as nanosensors, nanoimaging agents, and nanomedical platforms. Spanning diagnostics and treatment-focused applications in sporadic and familial Alzheimer’s and Parkinson’s disease, epilepsy, the diagnosis of neuro parasite-driven pathologies, and avante garde label-free Raman spectroscopic techniques, the contents make for a compelling read.

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I am confident that this collection of chapters under the “Neuro” ambit will benefit not only a graduate student, researcher, academician, healthcare worker, and drug developer in the field but will also be of interest to members of the general public. Congratulations to the editors and the authors for an enlightening, scintillating, and technically advanced compilation. Mahesh Narayan, FRSC, is a biophysicist and Professor in the Department of Chemistry and Biochemistry at UTEP. His current research interests include protein misfolding, neurodegenerative onset, and mechanisms of diagnosis and intervention, including nanoscopic probes and platforms. In addition, he has interests in chemical education and drug design and development and is a proponent of back-­ of-­the-envelope calculations for most problems. He enjoys authorship and co-­ authorship of ∼130 research and review articles, book chapters, and educational works.

Department of Chemistry and Biochemistry UTEP, El Paso, TX, USA

Mahesh Narayan

Preface

The human brain is an intricate and complex organ responsible for our thoughts, emotions, and actions. Neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and stroke, disrupt the normal functioning of the brain, leading to a range of debilitating symptoms. These disorders affect millions of people worldwide, causing significant suffering and posing a substantial economic burden. Traditionally, the treatment of neurological disorders has been challenging due to the difficulty of delivering drugs to the brain, which is protected by the blood–brain barrier (BBB). This barrier selectively restricts the passage of molecules from the bloodstream into the brain, making it difficult for conventional drugs to reach their target sites. In recent years, nanotechnology has emerged as a promising approach to overcoming these challenges and revolutionizing the theranostics of neurological disorders. Nanoparticles, which are particles with a size of 1–100 nm, offer unique properties that make them ideal for drug delivery to the brain. They can be designed to cross the BBB, encapsulate drugs, and release them in a controlled manner, maximizing their therapeutic efficacy and minimizing side effects. This book, titled Theranostic Applications of Nanotechnology in Neurological Disorders, delves into the exciting advancements in nanotechnology that are transforming the treatment and diagnosis of neurological disorders. It encompasses a comprehensive overview of the field, covering topics from the challenges of neurological disorders to the latest nanotechnology-based approaches for theranostics. Due to the multi-disciplinary nature of this book, it is a combined product of efforts by two esteemed researchers in their own field. Dr. Akash Gautam, Assistant Professor of Neuroscience at the University of Hyderabad (India), has expertise in neurological disorders, whereas Dr. Vishal Chaudary, Assistant Professor of Physics at the University of Delhi (India), has an extensive record of research work in the field of nanotechnology. Our combined expertise and experience ensure that the book provides a comprehensive and up-to-date overview of the latest advancements in nanotechnology for neurological disorders. The book begins by exploring the challenges in the theranostics of neurological disorders, highlighting the limitations of conventional therapies and the potential of nanotechnology to address these limitations. It then delves into the rise of nanotechnology for neurological disorders, showcasing the various nanoparticle-based strategies for drug delivery, imaging, and therapy. A significant focus is placed on the implications of biosensors in the early detection of neuro-parasitic diseases, vii

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Preface

emphasizing the potential of nanotechnology to develop sensitive and specific diagnostic tools for these challenging infections. Additionally, the book explores green nanotechnology approaches for addressing neurodegenerative disorders, emphasizing the development of biodegradable and biocompatible nanomaterials. Nanotherapeutics for neurological disorders are extensively discussed, covering the use of nanoparticles to deliver drugs, gene therapy, and other therapeutic agents directly to the brain. The potential of nanotherapeutics in the prophylaxis and diagnosis of zoonotic diseases related to the nervous system is also explored, highlighting the role of nanotechnology in combating these emerging threats. Drug delivery for neurological disorders using nanotechnology is a key focus, with chapters dedicated to various nanoparticle-based delivery systems, including polymeric nanoparticles, lipid nanoparticles, and inorganic nanoparticles. The book also explores the use of nanotechnology and nature-sourced ingredients for tackling neurodegenerative diseases, emphasizing the potential of synergistic approaches combining nanomaterials with natural compounds. Deciphering the role of nanomedicines for the treatment and neurorestoration of ischemic stroke is a central theme, with chapters dedicated to the use of nanotechnology in stroke therapy, neuroprotection, and neurorestoration. Progress and prospects in Raman spectroscopy for detecting neurological disorders are also discussed, highlighting the potential of this non-invasive optical technique for early diagnosis and monitoring of neurological diseases. Nanotools for screening neurodegenerative diseases are extensively explored, covering the use of nanoparticles for the development of sensitive and specific diagnostic tools for these disorders. The design of therapeutic nanomaterials for the amelioration of Alzheimer’s disease is also discussed in detail, with chapters dedicated to various nanoparticle-based approaches for targeting specific aspects of the disease pathology. Finally, the book concludes by addressing the challenges of using nanotechnology for neurological disorders and exploring alternative solutions. It highlights the importance of safety and regulatory considerations, as well as the need for further research to optimize the efficacy and safety of nanotechnology-based therapies. Editors are sure that this comprehensive book will provide a valuable resource for researchers, clinicians, and students interested in the latest advancements in nanotechnology for neurological disorders. It offers insights into the challenges and opportunities in this rapidly evolving field and paves the way for future innovations that will transform the treatment and diagnosis of these debilitating conditions. Last but not least, both editors are thankful to all the authors for their timely contributions and to all the members of the production team for their continuous assistance during the publication process. Hyderabad, Telangana, India New Delhi, Delhi, India 

Akash Gautam Vishal Chaudhary

Contents

1

 Neurological Disorders and Challenges in Their Theranostics ������������   1 Prabhat Kumar, Dóra Zelena, and Akash Gautam

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 Rise of Nanotechnology for Neurological Disorders Management�������  31 Harshit Saxena, Akhilesh Kumar, Pooja Solanki, and K. Gowtham Bhandari

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Implications of Nano-Biosensors in the Early Detection of Neuroparasitic Diseases����������������������������������������������������������������������������  43 Shabir Ahmad Rather, Rashaid Ali Mustafa, Mohammad Vikas Ashraf, M. A. Hannan Khan, Shoeb Ahmad, and Zahoor Ahmad Wani

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Green Nanotechnology for Addressing Neurodegenerative Disorders����������������������������������������������������������������������������������������������������  85 Bindiya Barsola, Shivani Saklani, and Diksha Pathania

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 Nanotherapeutics for Neurological Disorders ����������������������������������������  95 Bilachi S. Ravindranath and Ananya Grewall

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Role of Nanoparticles and Nanotherapeutics in the Diagnosis of Serious Zoonotic and Neurological Diseases �������������������������������������� 115 Nida Wazir, Maria Asghar, Sahar Younis, Muhammad Ahsan Naeem, Waqas Ahmad, Qaiser Akram, and Muhammad Akram Khan

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 Drug Delivery for Neurological Disorders Using Nanotechnology�������� 135 Sagnik Nag, Mahek Bhatt, Subhrojyoti Ghosh, Anuvab Dey, Srijita Paul, Shrestha Dutta, Sourav Mohanto, B. H. Jaswanth Gowda, and Mohammed Gulzar Ahmed

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 Nanotechnology and Nature-Sourced Ingredients for Tackling Neurodegenerative Diseases���������������������������������������������������������������������� 167 Verónica Rocha, Joana Ribeiro, Raúl Machado, and Andreia Gomes

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Deciphering the Role of Nanomedicines for the Treatment of Ischemic Stroke�������������������������������������������������������������������������������������� 193 Faizan Ahmad, Anik Karan, Navatha Shree Sharma, Vaishnavi Sundar, Richard Jayaraj, and Umme Abiha ix

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10 Raman  Spectroscopy for Detecting Neurological Disorders: Progress and Prospects������������������������������������������������������������������������������ 219 Mithun N, Megha Sunil, Meril Charles, Sanoop Pavithran M, Santhosh Chidangil, and Jijo Lukose 11 Nanotools  for Screening Neurodegenerative Diseases���������������������������� 251 Bakr Ahmed Taha, Mohd Hadri Hafiz Mokhtar, Retna Apsari, Adawiya J. Haider, Rishi Kumar Talreja, Vishal Chaudhary, and Norhana Arsad 12 Design  of Therapeutic Nanomaterials for Amelioration of Alzheimer’s Disease ���������������������������������������������������������������������������������� 267 Nibedita Pradhan and Tapan Kumar Si 13 Challenges  of Using Nanotechnology for Neurological Disorders and Alternate Solutions ���������������������������������������������������������������������������� 293 Swarnali Das, Rubai Ahmed, Sovan Samanta, Jhimli Banerjee, and Sandeep Kumar Dash

Editors and Contributors

About the Editors Akash Gautam  is an assistant professor at the Centre for Neural and Cognitive sciences, School of Medical Sciences, University of Hyderabad, India, since 2013. He earned his PhD from the department of zoology, Banaras Hindu University, India. His research interest is in neuroscience with a specialization in the neurobiology of learning and memory, molecular mechanisms of neurodegenerative disorders, synthesis of nanoformulations and herbal therapeutics for neurological disorders. He has been conferred several awards, including the International Brain Research Organization, the International Society for Neurochemistry, and the Department of Science and Technology, India. He has more than 10 years of teaching experience for inter-disciplinary courses like cognitive science, biochemistry, research methodology and statistics, and molecular neuroscience. He has also published various research articles in the peer-reviewed international journal, a few book and book chapters. He is a member of many international scientific societies and organizations, notably the Indian Science Congress Association, Indian Academy of Neurosciences, Society of Biological Chemists, India, Society for Neurosciences, Molecular and Cellular Cognition Society, International Society for Neurochemistry, Society for Neurochemistry, India. Vishal Chaudhary  is an assistant professor of physics at the University of Delhi since 2015, and a visiting associate professor at chemical engineering department, University of Johannesburg, South Africa. He has obtained his doctorate in condensed nano-matter physics from the department of physics and astrophysics, University of Delhi, New Delhi, India. His research interests include nanomaterials, green nanotechnology, sensors, environmental remediation, one health and non-­ invasive diagnosis. He has published various research articles, and a few books and book chapters. He has been listed in top 2% scientist in world and awarded with many prestigious awards including Agents of Change Award 2023 and SDG Service Award 2021. He is a member of various scientific advisory committees, associate editor/editorial board member of prestigious journals, and served as convenor of the research cell of the institution for two consecutive years.

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Contributors Umme Abiha  IDRP, Indian Institute of Technology, Jodhpur, Rajasthan, India All India Institute of Medical Sciences, Jodhpur, Rajasthan, India Faizan  Ahmad  Department of Medical Elementology and Toxicology, Jamia Hamdard University, Delhi, India Shoeb  Ahmad  Department of Biotechnology, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, India Waqas  Ahmad  Department of Clinical Sciences, University of Veterinary and Animal Sciences, Lahore, Narowal, Pakistan Mohammed Gulzar Ahmed  Department of Pharmaceutics, Yenepoya Pharmacy College and Research Centre, Yenepoya (Deemed to be University), Mangaluru, Karnataka, India Rubai Ahmed  Department of Physiology, University of Gour Banga, Malda, West Bengal, India Qaiser Akram  Department of Pathobiology, University of Veterinary and Animal Sciences, Lahore, Narowal, Pakistan Retna  Apsari  Department of Physics, Faculty of Science and Technology and Department of Engineering, Faculty of Advanced Technology and Multidiscipline, Universitas Airlangga, Jl. Mulyorejo, Surabaya, Indonesia Norhana  Arsad  Photonic Technology Laboratory, Faculty of Engineering and Built Environment, Department of Electrical, Electronic and Systems Engineering, Universiti Kebangsaan Malaysia, UKM, Bangi, Malaysia Maria  Asghar  University of Veterinary and Animal Sciences, Lahore, Narowal, Pakistan Mohammad Vikas Ashraf  Department of Biotechnology, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, India Jhimli  Banerjee  Department of Physiology, University of Gour Banga, Malda, West Bengal, India Bindiya  Barsola  School of Biological and Environmental Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, India K. Gowtham Bhandari  Department of Pharmacology, KLE College of Pharmacy, Bangalore, India Mahek  Bhatt  Department of Life Sciences, School of Arts and Science, Ahmedabad University, Ahmedabad, Gujarat, India

Editors and Contributors

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Meril Charles  Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka, India Vishal  Chaudhary  Research Cell and Department of Physics, Bhagini Nivedita College, University of Delhi, New Delhi, India Santhosh  Chidangil  Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka, India Sandeep  Kumar  Dash  Department of Physiology, University of Gour Banga, Malda, West Bengal, India Swarnali Das  Department of Physiology, University of Gour Banga, Malda, West Bengal, India Anuvab  Dey  Department of Biological Sciences and Bioengineering, IIT Guwahati, North Guwahati, Assam, India Shrestha Dutta  Department of Biotechnology, Amity Institute of Biotechnology, Amity University, Kolkata, West Bengal, India Akash  Gautam  Centre for Neural and Cognitive Sciences, University of Hyderabad, Hyderabad, India Subhrojyoti  Ghosh  Department of Biotechnology, IIT Madras, Chennai, Tamil Nadu, India Andreia  Gomes  Centre of Molecular and Environmental Biology (CBMA)/ Aquatic Research Network (ARNET) Associate Laboratory, Universidade do Minho, Campus de Gualtar, Braga, Portugal Institute of Science and Innovation for Bio-Sustainability (IB-S), Universidade do Minho, Campus de Gualtar, Braga, Portugal B.  H.  Jaswanth  Gowda  Department of Pharmaceutics, Yenepoya Pharmacy College and Research Centre, Yenepoya (Deemed to be University), Mangaluru, Karnataka, India Ananya Grewall  Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India Adawiya J. Haider  Applied Sciences Department/Laser Science and Technology Branch, University of Technology, Baghdad, Iraq Richard  Jayaraj  Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE Anik Karan  CL Lab LLC, Gaithersburg, MD, USA

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M.  A.  Hannan  Khan  Department of Zoology, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, India Muhammad Akram Khan  Faculty of Veterinary and Animal Science, Department of Veterinary Pathology, PMAS-Arid Agriculture University, Rawalpindi, Pakistan Akhilesh Kumar  Division of Medicine, ICAR-IVRI, Bareilly, India Prabhat  Kumar  Institute of Physiology, Medical School, University of Pécs, Pécs, Hungary Doctoral School of Basic Medicine, Medical School, University of Pécs, Pécs, Hungary Center of Neuroscience, University of Pécs, Hungary Jijo  Lukose  Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka, India Raúl Machado  Centre of Molecular and Environmental Biology (CBMA)/Aquatic Research Network (ARNET) Associate Laboratory, Universidade do Minho, Campus de Gualtar, Braga, Portugal Institute of Science and Innovation for Bio-Sustainability (IB-S), Universidade do Minho, Campus de Gualtar, Braga, Portugal N.  Mithun  Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka, India Sourav Mohanto  Department of Pharmaceutics, Yenepoya Pharmacy College and Research Centre, Yenepoya (Deemed to be University), Mangaluru, Karnataka, India Mohd  Hadri  Hafiz  Mokhtar  Photonic Technology Laboratory, Faculty of Engineering and Built Environment, Department of Electrical, Electronic and Systems Engineering, Universiti Kebangsaan Malaysia, UKM, Bangi, Malaysia Rashaid  Ali  Mustafa  Department of Zoology, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, India Muhammad  Ahsan  Naeem  Department of Basic Sciences, University of Veterinary and Animal Sciences, Lahore, Narowal, Pakistan Sagnik Nag  Department of Bio-Sciences, School of Bio-Sciences and Technology (SBST), Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India Diksha  Pathania  Department of Biotechnology, Markandeshwar University, Ambala, Haryana, India

MMEC,

Maharishi

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Srijita  Paul  Department of Microbiology, Gurudas College, Kolkata, West Bengal, India M.  Sanoop  Pavithran  Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka, India Nibedita  Pradhan  Department of Life Sciences, Kristu Jayanti College (Autonomous), India Shabir  Ahmad  Rather  Department of Zoology, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, India Bilachi S. Ravindranath  Manipal Institute of Technology, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India Joana Ribeiro  Centre of Molecular and Environmental Biology (CBMA)/Aquatic Research Network (ARNET) Associate Laboratory, Universidade do Minho, Campus de Gualtar, Braga, Portugal Verónica  Rocha  Centre of Molecular and Environmental Biology (CBMA)/ Aquatic Research Network (ARNET) Associate Laboratory, Universidade do Minho, Campus de Gualtar, Braga, Portugal Shivani  Saklani  School of Biological and Environmental Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, India Sovan  Samanta  Department of Physiology, University of Gour Banga, Malda, West Bengal, India Harshit Saxena  Division of Medicine, ICAR-IVRI, Bareilly, India Navatha  Shree  Sharma  Department of Surgery Transplant and Mary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Centre, Omaha, NE, USA Tapan  Kumar  Si  Department of Chemistry, Bidhan Chandra College, Asansol, India Pooja Solanki  Division of Medicine, ICAR-IVRI, Bareilly, India Vaishnavi  Sundar  Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA Megha Sunil  Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka, India Bakr Ahmed Taha  Photonic Technology Laboratory, Faculty of Engineering and Built Environment, Department of Electrical, Electronic and Systems Engineering, Universiti Kebangsaan Malaysia, UKM, Bangi, Malaysia

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Rishi  Kumar  Talreja  Vardhman Mahavir Medical College and Safdurjung Hospital, New Delhi, India Zahoor Ahmad Wani  Division of Veterinary Parasitology, SKUAST-K, Shuhama, Jammu and Kashmir, India Nida  Wazir  University of Veterinary and Animal Sciences, Lahore, Narowal, Pakistan Sahar Younis  Faculty of Veterinary Science, University of Agriculture, Faisalabad, Pakistan Dóra  Zelena  Institute of Physiology, Medical School, University of Pécs, Pécs, Hungary Center of Neuroscience, University of Pécs, Pecs, Hungary

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Neurological Disorders and Challenges in Their Theranostics Prabhat Kumar, Dóra Zelena, and Akash Gautam

Abstract

Neurological disorders encompass multifaceted and heterogeneous ailments that influence the whole body though the central and peripheral nervous systems. These conditions give rise to a variety of incapacitating symptoms, thereby exerting an important impact on the overall well-being of countless individuals across the globe. This book chapter provides an overview of the complex realm of neurological disorders and the formidable obstacles they present within the framework of theranostics, with the objective of tailoring personalized treatment. The foremost common neurological disorders will be covered, including but not limited to Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and epilepsy, accentuating their clinical pathophysiology and the profound onus they impose upon patients, carers, and healthcare systems. For timely identification of disease onset and precise categorization, diagnostic methodologies will be included, encompassing neuroimaging, cerebrospinal fluid biomarkers, and genetic profiling. However, the obstacles encountered in the development of efficacious theranostic strategies for neurological disorders will also be mentioned (e.g., drug delivery across the blood-brain barrier). The elucidation of emerging technoloP. Kumar Institute of Physiology, Medical School, University of Pécs, Pécs, Hungary Doctoral School of Basic Medicine, Medical School, University of Pécs, Pécs, Hungary Center of Neuroscience, University of Pécs, Pecs, Hungary D. Zelena Institute of Physiology, Medical School, University of Pécs, Pécs, Hungary Center of Neuroscience, University of Pécs, Pecs, Hungary A. Gautam (*) Centre for Neural and Cognitive Sciences, University of Hyderabad, Hyderabad, India e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_1

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gies, including nanomedicine, gene therapy, and precision medicine, presents promising avenues for surmounting these challenges and heralding a novel epoch of personalized therapeutics. By establishing a connection between diagnosis and treatment, researchers and clinicians can strive to offer more effective interventions to address the complex nature of neurological disorders. Keywords

Alzheimer’s disease · Parkinson’s disease · Neurological disorder · Neurodegenerative disorder · Brain tumors

1.1 Neurological Disorders: An Overview Before getting into the specifics of neurological conditions, it’s vital to understand the nervous system’s basic structure and function. The nervous system has two primary components: the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS comprises the brain and spinal cord, whereas the PNS includes the network of nerves that extend throughout the body. The nervous system serves a vital role in regulating physical functions, directing movements, processing sensory information, and facilitating communication between different regions of the body. This intricate system assumes a pivotal role in orchestrating and harmonizing the multifaceted functions of our corporeal entity. Any disruption of this complex neural network can lead to the development of neurological diseases with a plethora of symptoms, exerting an impact on an individual’s somatic, cognitive, and affective homeostasis (Nakase and Naus 2004; Hallett et al. 2022). The symptoms of these disorders exhibit a remarkable heterogeneity from prevalent afflictions like cephalalgia and migrainous episodes to intricate and incapacitating conditions such as epileptic seizures, neurodegenerative Alzheimer’s disease (AD) pathology, Parkinsonian (PD) motor impairments, and demyelinating multiple sclerosis. Neurological disorders, characterized by their intricate etiology, frequently arise from a complex interplay of genetic predispositions, environmental influences, and occasionally enigmatic triggers (Sorboni et al. 2022), summarized in Engel’s biopsychosocial model (Engel 1978) or the three-hit-theory (Daskalakis et al. 2013). The profound impact of neurological disorders extends beyond the affected individuals, encompassing their familial and communal spheres. The effective management and treatment of these conditions frequently necessitate the implementation of a multidisciplinary framework involving neurologists, psychiatrists, physical therapists, and various other healthcare professionals, as well as social workers (Singh et al. 2023). Comprehending the complexities inherent in neurological disorders is imperative to advance in diagnosis, treatment, and support systems, thereby augmenting the overall well-being and quality of life not only of those individuals who are impacted by such conditions but also the caregivers and family members. The persistent investigation and progress in medical science may illuminate these conditions, instilling optimism for enhanced interventions and superior outcomes in the forthcoming era (Simonato et al. 2013).

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1.2 Development of Neurological Disorders The general mechanisms behind neurological illnesses are summarized along the three-hit theory. In certain circumstances, the actual etiology of a neurological problem remains unknown, reflecting the complexity of these conditions (Shastry 2003). Through understanding the underlying biology, researchers are taking steps toward more effective interventions and customized therapies (Espay et al. 2018). 1. Genetic influences (first hit): Although only a few neurological disorders are monogenetically inherited (e.g., Huntington’s disease (HD) is caused by a mutation in the Huntingtin (HTT) gene, leading to the build-up of toxic proteins in neurons (Margolis and Ross 2003)), multigenic predisposition, that is, hereditary component, can often be detected, meaning that specific genetic changes might enhance an individual’s vulnerability to these conditions. For instance, mutations in the PARK2, PINK1, and LRRK2 genes have been associated with PD, altering essential physiological functions such as mitochondrial activity and protein breakdown (Kilarski et al. 2012; Nyutemans et al. 2010). 2. Environmental factors (second hit): Environmental effects can change the functioning of our body in the long term via epigenetic alterations, which entail changes in gene expression without affecting the underlying DNA sequence (Ahmad Mir et  al. 2023). Thus, an individual’s susceptibility or resilience to specific illnesses is affected. Epigenetic modifications have been related to ­diseases like schizophrenia and bipolar disorder, revealing insights into the intricate interplay between heredity and environment (Zelena 2012; La Rovere et al. 2019). All in all, genes and early environment influence brain development and, in this way, may determine the personality. In fact, some neurological disorders even called neurodevelopmental diseases, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). For instance, in ASD, mutations in genes like SHANK3 and FMR1 have been found, altering synaptic connections and neural communication (Mitchell 2011). However, intrauterine stress, infection, and drugs might be similar pathological factors (László et al. 2023). Examples of congenital neurological diseases include cerebral palsy and spina bifida as well (Sleigh et al. 2019). 3. Exacerbating stress (third hit): Acquired neurological disorders develop later in life and can be caused by factors such as infections (e.g., meningitis, encephalitis), traumatic injuries (e.g., traumatic brain injury (TBI)), autoimmune reactions (e.g., multiple sclerosis (MS)), and degenerative processes (e.g., AD, PD). One of the popular theories is neuroinflammation, characterized by the activation of immune cells within the CNS.  Neuroinflammatory processes are observed in conditions such as MS; the immune system mistakenly targets the protective myelin layer around nerve fibers, leading to communication failure between neurons. AD is also connected with neuroinflammation, where the formation of beta-amyloid plaques induces an immunological response that adds to neuronal damage (Gilhus and Deuschl 2019). The investigation of immune-modulating

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therapies is being undertaken in order to effectively manage these diseases, with the primary objective of attenuating inflammatory responses and ameliorating associated symptoms (West et al. 2019). However, AD is also considered to be type 3 diabetes mellitus or diabetes of the brain, highlighting another popular theory of disease development, the metabolic origin (Nguyen et al. 2020). Nevertheless, causative factors along the three-hit theory might lead to neurotransmitter imbalance or protein misfolding and aggregations, which might be prospective therapeutic targets. For example, in PD, there’s evidence of changed levels of dopamine (Valenzuela et  al. 2011). In disorders like AD, PD, and amyotrophic lateral sclerosis (ALS), proteins (beta-amyloid, alphasynuclein, and TDP-43, respectively) misfold and clump together, generating toxic aggregates that disrupt cellular function and ultimately lead to neuronal death (Shastry 2003).

1.3 Clinical Aspects of Neurological Disorders Ranging from moderately common to exceedingly unusual, neurological disorders can have a tremendous impact on an individual’s quality of life as well as create substantial issues for the medical profession. From a medical perspective, their symptoms, diagnosis, and potential therapies based on their possible causation should be highlighted (Nakase and Naus 2004). The symptoms of neurological conditions vary widely, depending on the individual disorder and the area of the nervous system affected. Common symptoms include changes in motor function (such as weakness or tremors), sensory disturbances (such as numbness or tingling), cognitive impairments (such as memory loss), and disruptions in speech or language ability. Diagnosing neurological problems demands a comprehensive approach. Physicians generally rely on a combination of medical history, physical examinations, and modern diagnostic technologies such as magnetic resonance imaging (MRI), computed tomography (CT) scans, and electroencephalography (EEG) testing. These tests help to visualize the anatomy and function of the brain and nervous system, aiding in a proper diagnosis (Boffeli and Guze 1992). Due to its heterogenous nature and broad symptom profile, the therapy is also variable, often targeting the neurotransmitters (e.g., dopaminergic system in case of PD, cholinergic system in AD). Through the exploration of the complex neural networks associated with well-­ known neurological disorders (Fig.  1.1), our objective is to shed light upon the intricacies, obstacles, and aspirations that characterize our endeavor to enhance our comprehension and control of these enigmatic neurological disorders that impact the lives of individuals and families across the globe.

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Fig. 1.1  Common neurological disorders

1.3.1 Neurodegenerative Diseases 1.3.1.1 Alzheimer’s Disease AD, an incapacitating neurodegenerative disorder, represents a prominent etiology of cognitive decline in the geriatric population. The gradual deterioration of cognitive functions is observed, commencing with memory deficits and subsequently advancing to the impairment of reasoning abilities, language skills, and the execution of routine daily tasks (Van Dyck et al. 2023). As the progression of AD ensues, affected individuals frequently encounter challenges in the realm of recognizing familiar individuals, necessitating a heightened level of care and support (Dubois et al. 2021). The pathological hallmarks of this disorder are distinguished by the atypical accumulation of amyloid plaques and tau tangles within the cerebral cortex, thereby impeding intraneuronal communication and ultimately culminating in neuronal demise. Thus, originally, the diagnosis was post-mortem; however, nowadays, positron emission tomography (PET), an advanced brain imaging technique, allows us to detect these plaques in vivo in the patients, thereby allowing the follow of the progression (Wang et  al. 2023). Although a definitive cure remains elusive, it is worth noting that timely identification, lifestyle modifications, and administration of pharmacological interventions hold promise in ameliorating symptoms and

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enhancing the overall well-being of individuals impacted by this condition, as well as those entrusted with their care (Scheltens et al. 2021).

1.3.1.2 Parkinson’s Disease It is an insidious neurodegenerative condition that manifests as a gradual deterioration of dopaminergic neurons within the substantia nigra, a crucial brain region of motor function and coordination (Weintraub et al. 2022). Prominent clinical symptoms commonly observed in patients with this condition encompass resting tremors bradykinesia, characterized by a reduction in the speed of voluntary movements, rigidity, and postural instability. The fundamental neuropathological mechanism entails the aggregation of alpha-synuclein protein, which undergoes misfolding and forms Lewy bodies. These aberrant protein aggregates disrupt the normal functioning of cells and ultimately lead to the demise of neurons (Jankovic and Tan 2020). The clinical diagnosis of PD remains challenging and depends mainly on clinical features and imaging tests (among others, PET) (Martin et al. 2023). Efficient and specific biomarkers in different tissues and biofluids, along with the current clinical, biochemical detection methods, are crucial for the diagnosis. The sensitivity and specificity of single biomarkers are limited, and selecting appropriate indicators for combined detection can improve the diagnostic accuracy of PD (Ma et  al. 2023; Bloem et al. 2021). 1.3.1.3 Huntington’s Disease It is an autosomal dominant neurodegenerative disorder characterized by a genetic mutation in the HTT gene, resulting in the synthesis of aberrant huntingtin protein. The aberrant protein exhibits a propensity for intracerebral aggregation, with a predilection for the basal ganglia and cortex regions, thereby exerting its primary influence (Tabrizi et al. 2022b). HD is characterized by the gradual onset and progression of motor dysfunction, notably presenting as chorea, which refers to the presence of involuntary movements. Additionally, individuals with HD experience cognitive decline, marked by a deterioration in cognitive abilities, and may exhibit various psychiatric symptoms. As the pathological condition advances, affected individuals undergo a substantial decline in functional abilities, culminating in profound deficits in both motor control and cognitive processes (Tabrizi et al. 2022a). As a monogenic disorder, its diagnosis is based upon the detection of the mutation. At present, a definitive cure for HD remains elusive. However, the medical community has made strides in developing symptomatic interventions and offering genetic counselling services. These approaches aim to address the development of symptoms effectively and offer valuable guidance to individuals and families who may be at risk of inheriting the condition (Singh et al. 2022). 1.3.1.4 Motor Neuron Disease: Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) ALS, colloquially referred to as Lou Gehrig’s disease, represents a profoundly debilitating neurodegenerative condition typified by the progressive degeneration of motor neurons within the CNS, encompassing both the brain and spinal cord

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(Feldman et  al. 2022). The observed outcome manifests as a gradual decline in muscular strength, accompanied by the development of spasticity, culminating in a state of complete paralysis. As both the upper motor neurons and lower motor neurons are implicated, this dual impact on motor neuron populations culminates in respiratory failure as the disease progresses (Johnson et al. 2022). The precise etiology of the condition remains enigmatic in the majority of instances, albeit certain cases have been associated with genetic mutations (Brenner and Freischmidt 2022). ALS is a clinical diagnosis using electrophysiology to objectively establish a lower motor neuronopathy and neuroimaging of the brain and spine to exclude other possibilities (Ilieva et  al. 2023). Presently, the absence of a definitive cure for ALS remains a challenge (Mead et al. 2023). On the other hand, SMA is an autosomal recessive neurodegenerative disease caused by a deficiency of survival of motoneuron protein due to a mutation or deletion of the SMN1 gene. The protein deficiency leads to degeneration of ⍺-motoneurons in the anterior horns of the spinal cord and, consequently, to gradual muscle atrophy. In addition, in more severe forms of SMA, additional cell and tissue types are affected, causing symptoms unrelated to motor neurons, like impaired bone development, defects in angiogenesis, and vascular maturation. SMA is a progressive and heterogeneous disease. Age of onset, clinical severity, and life expectancy can differ. Without appropriate therapy, it leads to muscle weakness, paralysis, and, consequently, in severe cases, death as a result of respiratory failure (Lejman et al. 2023).

1.3.2 Neurodevelopmental Disorders 1.3.2.1 Autism Spectrum Disorder ASD affects how people interact with others, communicate, learn, and behave. Although autism can be diagnosed at any age, it is described as a “developmental disorder” because symptoms generally appear in the first 2 years of life. The major problem is in social communication, accompanied by restricted interest and repetitive behavior (László et al. 2023). However, it is called a spectrum disorder because there is wide variation in the type and severity of symptoms people experience. The early diagnosis is crucial for timely intervention and improved long-term outcomes. Besides questionnaires (Okoye et  al. 2023), eye tracking might also be used (Shishido et al. 2019). 1.3.2.2 Schizophrenia Although ASD and schizophrenia (SCZ) might have a common origin (ASD was even called childhood SCZ in the past), there are substantial differences. Although the core symptoms of SCZ include social problems, and cognitive disabilities, positive signs, like hallucinations and delusions, can also occur. Moreover, the onset is typically during adolescence and not right after birth, and SCZ manifests in bursts. Between the episodes the people might be normal. Till now, the diagnosis is based on clinical symptoms; any biomarkers found so far are not unique. Based upon

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multifaceted causation, the better-acting second-third generation antipsychotics target not only the dopaminergic system but a wide array of neurotransmitters, including serotonin and histamine (Glatt et al. 2019).

1.3.2.3 Attention-Deficit/Hyperactivity Disorder ADHD is usually first diagnosed in childhood and often lasts into adulthood. Children with ADHD may have trouble paying attention, controlling impulsive behaviors (may act without thinking about what the result will be), or be overly active. The cause(s) and risk factors for ADHD are unknown, but current research shows that genetics plays an important role. Other possible risk factors are brain injury and intrauterine exposure to, for example, lead, alcohol, and tobacco, leading to premature delivery and low birth weight (Núñez-Jaramillo et al. 2021). 1.3.2.4 Tourette Syndrome Tourette syndrome is a complex neurological condition that develops as repetitive and involuntary motor and vocal tics. These abrupt and involuntary movements and vocalizations can exhibit a range of intensity and occurrence, frequently appearing during the early stages of development (Lamanna et al. 2023). The precise etiology of Tourette’s syndrome remains unclear, although current understanding suggests a complex interplay between genetic predisposition and environmental influences. While Tourette’s syndrome can have a significant impact on daily functioning, individuals with this condition can still lead meaningful lives with effective management strategies and appropriate support (Chou et al. 2023).

1.3.3 Infections Infectious diseases remain a significant health burden worldwide. Although they might target different organs, leading to a wide range of symptoms, but in many cases, the neurological symptoms dominate, and these might be the most problematic ones, often leading to life-threatening events. The cause in these cases is generally known (a virus, bacteria, or parasite), and the diagnosis is dependent on the detection of the pathogen. The symptoms may vary according to the tropism of the different pathogens.

1.3.3.1 According to the Most Affected Brain Area: Encephalitis and Meningitis Encephalitis is a rapid-onset inflammatory condition affecting the brain, predominantly triggered by viral pathogens or immune-mediated reactions. The observed clinical symptoms encompass pyrexia, cephalalgia, perturbed cognitive state, and impairments in the neurological domain (Abboud et  al. 2021). In instances of heightened severity, it is plausible for individuals to experience convulsive episodes, motor impairment, or a state of profound unconsciousness. The prompt recognition and intervention of neurological conditions are of paramount importance in order to attenuate potential complications within the nervous system and maximize the overall well-being of the patient (Uy et al. 2021).

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Meningitis is an infectious pathology that manifests as an inflammatory response within the meninges, which are the anatomical structures responsible for safeguarding the brain and spinal cord. Usually attributed to the pathogenic activity of bacteria or viruses, this condition develops with clinical symptoms such as pyrexia, intense cephalalgia, and nuchal rigidity. The expeditious identification and subsequent administration of suitable therapeutic interventions, such as the targeted use of antibiotics in cases of bacterial meningitis, are of utmost importance in mitigating the potential for adverse outcomes and neuronal impairment (Hasbun 2022).

1.3.3.2 According to the Pathogens 1.3.3.2.1 Virus`es 1.3.3.2.1.1 Rabies

Rabies is a neurotropic viral infection, predominantly disseminated via the inoculation of infected saliva into the host’s bloodstream, typically occurring through the bite of infected mammalian species, with dogs being the most prevalent reservoir. The viral pathogen has the capacity to infiltrate the intricate network of the CNS, thereby instigating a myriad of neurologically manifested symptoms (Rupprecht et al. 2022). The propagation of this pathogen occurs via the transmission along the intricate network of peripheral nerves, ultimately reaching the CNS and inducing the pathological condition known as encephalitis (Acharya et  al. 2020). The observed clinical presentation exhibits a rapid progression of symptoms, characterized by cognitive impairment, perceptual disturbances such as hallucinations, motor dysfunction leading to paralysis, and ultimately an unfavorable outcome if timely intervention is not administered. Once neurological symptoms manifest, the prognosis for individuals afflicted with rabies is overwhelmingly dire, with an exceedingly high fatality rate (Gold et al. 2020). 1.3.3.2.1.2 HIV

The human immunodeficiency virus (HIV) has been observed to exert deleterious effects on the immune system, leading to acquired immunodeficiency syndrome (AIDS), thereby heightening susceptibility to various infections and impeding the vigilant immune surveillance mechanisms operating within the intricate network of the nervous system. Consequently, the symptoms of HIV-associated neurocognitive disorders (HAND) may ensue precipitating cognitive impairments, motor dysfunction, and neuropathic pain. The timely initiation of antiretroviral therapy has been shown to effectively attenuate the neurological complications associated with HIV/ AIDS, thereby enhancing the overall quality of life experienced by affected individuals (Wahl and Al-Harthi 2023). 1.3.3.2.2 Neuroparasites The symptoms may be a combination of inflammation and signs of local brain damage induced function loss in the CNS/PNS structure.

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1.3.3.2.2.1 Echinococcosis

It is an affliction stemming from the infestation of tapeworms belonging to the taxonomic genus Echinococcus, representing a zoonotic parasitic ailment. The larval stages of these tapeworms have been observed to parasitize mammals, leading to the development of cystic structures filled with fluid within critical anatomical sites (Autier et al. 2023). Human infection is initiated by the process of ingestion of food that has been contaminated or through direct contact with animals that are carrying the infectious agent. Echinococcosis represents a substantial public health concern owing to its capacity for inducing profound organ impairment and giving rise to intricate surgical intricacies (Wang et al. 2022). 1.3.3.2.2.2 Schistosomiasis

It is an often-overlooked tropical disease that arises because of the infestation of human blood vessels by parasitic flatworms known as schistosomes. Transmission is facilitated through the intermediary of freshwater snails, whereby the larvae effectively breach the epidermal barrier upon exposure to water sources contaminated with infectious agents (Díaz et al. 2023). Prolonged and persistent infection has the potential to induce profound structural and functional impairments within vital organs. Schistosomiasis continues to pose a significant global health challenge, thereby requiring the implementation of comprehensive and integrated control strategies (Aziz et al. 2022). 1.3.3.2.2.3  Cerebral Malaria

It represents a severe and frequently lethal disorder induced by Plasmodium falciparum malaria, exerting its deleterious effects on the vasculature of the brain. The adhesion of infected red blood cells to the endothelial lining of blood vessels elicits a cascade of inflammatory responses, ultimately resulting in compromised hemodynamics. Consequently, this vascular dysfunction precipitates a range of neurological signs, including, but not limited to seizures and coma. The prompt administration of therapeutic interventions is of utmost importance to mitigate the risk of fatality in individuals who have been impacted (Adams and Jensen 2022). 1.3.3.2.2.4  Human African Trypanosomiasis

Human African trypanosomiasis, commonly known as sleeping sickness, is a debilitating affliction resulting from the parasitic infestation of Trypanosoma parasites, which are primarily transmitted via the bites of tsetse flies. The progression of this phenomenon occurs in a biphasic manner, characterized by neurological symptoms, notably disruptions in sleep patterns, during the latter stage. In the absence of appropriate intervention the condition may lead to a potentially life-threatening outcome. The primary emphasis of control endeavors lies in the timely identification and pharmacological intervention aimed at averting the signs of grave complications (Bernhard et al. 2022).

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1.3.3.2.2.5  American Trypanosomiasis

Colloquially referred to as Chagas disease, it is a pathogenic condition that arises from the infestation of the protozoan parasite Trypanosoma cruzi within the human host. Triatomine bugs primarily facilitate the transmission of the pathogen, although alternative modes of transmission include blood transfusion, organ transplantation, and congenital transmission. Prolonged infection may lead to various complications affecting both the cardiac gastrointestinal systems and CNS. The effective management of diseases necessitates the implementation of vector control strategies alongside timely diagnosis and treatment interventions (Hamer and Saunders 2022). 1.3.3.2.2.6 Toxoplasmosis

Toxoplasmosis is an infectious disease characterized by the presence of the protozoan parasite Toxoplasma gondii within the host organism. The transmission of the pathogen can occur via the oral route, specifically through the ingestion of food that has been contaminated with the pathogen or through direct contact with fecal matter from infected feline hosts. Although frequently lacking noticeable symptoms, this condition presents inherent dangers to individuals with compromised immune systems and expectant mothers, potentially resulting in significant neurological and ocular ramifications. Preventive measures encompass the implementation of appropriate protocols for food handling and maintenance of optimal hygiene practices (Zhang et al. 2022). 1.3.3.2.2.7 Neurocysticercosis

It refers to a pathogenic condition characterized by the infiltration of the CNS by the larval stage of the tapeworm Taenia solium. The symptoms arise because of the consumption of food or water compromised by harmful agents. The formation of larval cysts within the cerebral region has been observed to give rise to a spectrum of neurological symptoms, notably including the occurrence of seizures. The implementation of accurate diagnostic procedures and effective therapeutic interventions is of paramount importance in mitigating the risk of potential complications (Del Brutto 2022).

1.3.4 Autoimmune Diseases 1.3.4.1 Multiple Sclerosis MS is a persistent autoimmune neurologic condition distinguished by the demyelination of the CNS, leading to compromised intercellular communication among neurons. The development of symptoms exhibits considerable heterogeneity, encompassing a broad spectrum of clinical presentations (Hauser and Cree 2020). These may encompass a state of heightened somatic and mental exhaustion, compromised muscular strength, challenges in motor coordination, and perturbations in sensory perception. The precise etiology of MS remains elusive, as the underlying

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mechanisms driving its pathogenesis have yet to be fully elucidated (McGinley et al. 2021). This complex neurological disorder commonly manifests in individuals during early adulthood, heralding a progressive course characterized by a gradual accrual of disability over the course of time (Attfield et al. 2022).

1.3.4.2 Guillain-Barre Syndrome Guillain-Barre syndrome (GBS) is a pathophysiological condition that manifests as an autoimmune disorder wherein the immune system exhibits aberrant behavior by launching an assault on the PNS. This physiological testimony is indicative of compromised muscular function, accompanied by sensory disturbances characterized by tingling sensations (Shahrizaila et al. 2021). In instances of heightened severity, a state of paralysis may ensue. GBS, a neurological disorder, frequently manifests after viral infections and poses a significant risk to individuals’ lives as a result of its impact on respiratory musculature. The expeditious implementation of medical intervention is imperative for facilitating the process of recuperation (Leonhard et al. 2019).

1.3.5 Brain Tumors Brain tumors, also referred to as intracranial neoplasms, manifest as the atypical proliferation of cells within the intricate neural tissue of the brain. Tumors can exhibit either benign or malignant characteristics arising from diverse cellular lineages (Vienne-Jumeau et al. 2019). A special form, glioma, is a neoplastic growth that arises primarily from the glial cells within the brain. Categorized based on histological characteristics, gliomas encompass both low-grade neoplasms, characterized by a relatively indolent growth pattern, and high-grade tumors, which exhibit a more aggressive and rapid progression. The expression of symptoms is contingent upon the precise anatomical localization of the neoplastic growth (similarly to neuro-parasites), thereby encompassing a diverse array of potential clinical presentations, which may encompass cephalalgia, epileptic episodes, and impairments in neurological function. The diagnostic process typically encompasses the utilization of neuroimaging techniques, such as MRI or CT, in conjunction with the performance of a biopsy procedure. The available treatment modalities consist of surgical intervention, radiation therapy, and chemotherapy, which are administered based on the specific attributes of the tumor (Ostrom et al. 2019; Li et al. 2022).

1.3.6 Prevalent Brain Disorders with Variable Origin 1.3.6.1 Stroke Stroke, a perturbation of cerebrovascular dynamics, manifests when the delicate equilibrium of cerebral blood supply is compromised, precipitated by either an occlusion-induced ischemic event or a hemorrhagic episode. The development of rapid neuronal degeneration ensues, leading to a constellation of clinical symptoms

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encompassing motor impairment, speech dysfunctions, and perturbations in the state of consciousness. The prompt and immediate administration of medical intervention is of utmost importance in order to mitigate potential cerebral harm and mitigate subsequent functional impairments (Rexrode et al. 2022).

1.3.6.2 Traumatic Brain Injury TBI is a complex neurobiological disorder that arises because of external mechanical forces impacting the cranium, thereby inducing a cascade of pathophysiological events that disrupt normal brain functioning. The spectrum of TBI severities varies from mild concussions to more severe cases that can result in enduring impairments in cognitive, physical, or emotional functioning. The diagnostic process entails neuroimaging techniques, while the therapeutic approach centers around the mitigation of secondary neuronal harm, facilitation of recuperation, and management of concomitant symptoms (Maas et al. 2022). 1.3.6.3 Epilepsy Epilepsy is a complex neurological condition that manifests as a recurring and unpredictable occurrence of seizures, which can be attributed to atypical electrical discharges within the brain. The heterogeneity of seizure types and their corresponding degrees of severity engender diverse symptoms that exert profound effects on the domains of consciousness, motor function, and sensory perception. The diagnostic process encompasses a comprehensive clinical evaluation alongside the EEG techniques. The therapeutic approach for seizure control encompasses the administration of antiepileptic medications together with potential interventions such as surgical procedures or neuromodulation techniques (Rho and Boison 2022). 1.3.6.4 Migraine Migraine is a complex neurological condition that develops as recurring and severe headaches, commonly accompanied by symptoms like nausea, vomiting, and sensitivity to light. It encompasses atypical neural activity, which influences both vascular and nervous systems (Steiner and Stovner 2023). Migraines have the potential to significantly disrupt daily life; therefore, it is in the focus of ongoing research in the field of neurosciences. Both genetic and environmental factors are known to play substantial roles in the development of migraines (Al-Hassany et al. 2023). 1.3.6.5 Neuropathy A neurological condition, a condition that affects the transmission of signals between the brain and the body, influencing presumably the PNS, can significantly impair sensory and motor functions, resulting in a diverse array of symptoms such as nociception, hypoesthesia, paresthesia, and muscular debilitation (Shamsnajafabadi et al. 2023). This condition can arise from a multitude of factors, such as diabetes, infections, toxins, or autoimmune disorders, among others. Effective management and treatment strategies are often necessary to alleviate its impact (Galiero et al. 2023).

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1.4 Available Treatment Options for Neurological Disorders The treatment of neurological conditions depends on the specific condition and its underlying causes. Some disorders have specialized drugs that help alleviate symptoms or slow down the progression of the disease. For instance, pharmaceuticals like levodopa can alleviate motor symptoms in PD patients, whereas antiepileptic treatments help manage seizures in epilepsy patients (Thakur et al. 2016). In circumstances where drugs are insufficient, alternative therapeutic methods may be sought. Physical therapy, occupational therapy, and speech therapy can help people restore lost abilities and enhance their overall quality of life. Surgical procedures might also be essential for specific illnesses, such as deep brain stimulation (DBS) surgery for PD or removal of seizure-prone brain tissue in case of epilepsy (Simonato et al. 2013). Understanding the molecular causes behind neurological illnesses gives options for creating tailored therapeutics. Advances in genome editing tools like CRISPR-­ Cas9 hold promise for repairing genetic mutations responsible for some illnesses. In the field of PD, emerging treatments are focused on restoring dopamine levels using gene therapy and stem cell transplantation (Kampmann 2020). For disorders involving protein misfolding, researchers are studying medicines that can prevent aggregation or improve protein clearance. Small compounds, antibodies, and gene-based therapeutics are being studied as potential techniques to attack these fundamental systems. Additionally, neuroinflammation-targeted treatments are being developed to decrease the immune response in illnesses including MS and AD. Modulating immune cell activity and boosting neuroprotective mechanisms are major areas of focus (So et al. 2019). Thanks to breakthroughs in medical research and technology, various powerful treatments have been discovered to manage and alleviate the symptoms of these conditions (Heidenreich and Zhang 2016). Here, we look at the essential therapies for some of the most prevalent neurological disorders (Table 1.1).

1.4.1 Neurodegenerative Disorders 1.4.1.1 Alzheimer’s Disease While a cure remains elusive, therapeutic options focus on treating symptoms and enhancing the patient’s quality of life. Cholinesterase inhibitors such as Donepezil, Rivastigmine, and Galantamine are often administered to boost neurotransmitter levels and improve cognitive performance. Memantine, an NMDA receptor antagonist, helps control glutamate activity in the brain. Behavioral therapy and support from caregivers play a significant role in sustaining cognitive function and emotional well-being (Vaz and Silvestre 2020). 1.4.1.2 Parkinson’s Disease The gold standard treatment for PD is Levodopa, a dopamine replacement drug that helps alleviate motor symptoms. Dopamine agonists like Pramipexole and

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Table 1.1  Available treatment for some of the most prevalent neurological disorders Neurological diseases Alzheimer’s disease

Parkinson’s disease

Huntington’s disease

Amyotrophic lateral sclerosis (ALS)

Epilepsy

Migraine

Multiple sclerosis

Neuropathy

Stroke

Tourette syndrome

Available treatment •  Behavioral therapies •  Cholinesterase inhibitors (Donepezil, Rivastigmine, Galantamine) •  NMDA receptor antagonist (Memantine) •  Supportive care •  Dopamine replacement therapy (Levodopa) •  Dopamine agonists (Pramipexole, Ropinirole) •  MAO-B inhibitors (Selegiline, Rasagiline) •  Deep brain stimulation (DBS) •  Physical therapy and exercise •  Tetrabenazine and Deutetrabenazine (to manage chorea) •  Psychotherapy and support groups •  Supportive care for symptom management •  Riluzole and Edaravone (to slow disease progression) •  Supportive care for symptoms (physical therapy, speech therapy, breathing assistance) •  Assistive devices •  Antiepileptic drugs (Phenytoin, Carbamazepine, Valproate, Lamotrigine, etc.) •  Ketogenic diet vagus nerve stimulation •  Surgery (for some cases) •  Responsive neurostimulation (RNS) •  Pain relievers (Ibuprofen, Acetaminophen) •  Triptans (Sumatriptan, Rizatriptan) •  Preventive medications (Beta-blockers, Antidepressants) •  Lifestyle changes and triggers avoidance •  Disease-modifying therapies (Interferons, Glatiramer acetate, Fingolimod, etc.) •  Corticosteroids for relapse management •  Symptomatic treatments (muscle relaxants, physical therapy, speech therapy) •  Immunomodulatory treatments •  Pain medications (Gabapentin, Pregabalin) •  Antidepressants (Amitriptyline, Duloxetine) •  Lifestyle changes (blood sugar control for diabetic neuropathy) •  Physical therapy •  Clot-dissolving medications (Alteplase) •  Thrombectomy (mechanical removal of clots) •  Rehabilitation (physical therapy, speech therapy, occupational therapy) •  Medications to manage risk factors (Antihypertensives, Anticoagulants) •  Behavioral therapy (cognitive behavioral intervention for tics) •  Medications (antipsychotics, alpha agonists) •  Deep brain stimulation (in severe cases)

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Ropinirole replicate dopamine’s actions. MAO-B inhibitors such as Selegiline and Rasagiline slow dopamine breakdown. In more advanced cases, DBS involves implanting electrodes in specific brain locations to control aberrant neural activity. Physical therapy and exercise aid in controlling symptoms and improving mobility. Although a definitive cure for PD remains elusive, it is worth noting that various therapeutic interventions have demonstrated the potential to ameliorate symptoms and augment the overall well-being of afflicted individuals (Müller and Möhr 2019).

1.4.1.3 Huntington’s Disease Although genetic therapy would be a logical approach in a known monogenetic disorder, as the mutation affects the whole body, in utero, gene therapy should be used. At present, genetic diagnosis might prevent the birth of affected individuals. Although no specific treatment for HD exists, Tetrabenazine and Deutetrabenazine target chorea, a hallmark symptom, by modulating dopamine levels. Psychotherapy and support groups help address emotional and cognitive issues. As the disease develops, supportive care focuses on symptom control and enhancing the patient’s well-being (Wyant et al. 2017). 1.4.1.4 Motor Neuron Diseases For ALS certain therapeutic interventions, such as Riluzole and Edaravone, are licensed drugs to decrease disease progression by lowering neuron excitotoxicity and oxidative stress, respectively. Symptomatic therapies involve physical therapy, speech therapy, and respiratory support equipment to increase the patient’s functional capacity. Supportive care and palliative interventions are needed to enhance the patient’s quality of life. These interventions hold promise in affording patients a degree of respite from the burdens imposed by this debilitating condition (Zarei et al. 2015). For SMA, only in 2016 was the first drug, nusinersen, approved by the FDA. It is unique as this antisense oligonucleotide (ASO) target RNA. Although ASO-based therapies are currently used to treat a variety of conditions, for example, for hepatitis C virus or for Duchenne muscular dystrophy, their main limitations are their short half-life, the need for lifelong repeated dosing, and their inability to cross the blood-brain barrier. In 2019, the second FDA-approved therapy was Zolgesma, a gene replacement therapy using adeno-associated viral vectors (AAV) for gene transfer. The advantage of this method is that a single injection might cure the disorder, and AAVs do not induce any known disorders and do not significantly activate our immune system. However, intrathecal treatment is desirable to reach appropriate concentration on target areas as well as to avoid off-target gene incorporation (Lejman et al. 2023). Nevertheless, AAV vectors provide a valuable tool not only for the treatment of monogenic disorders but also for other symptoms, including PD and AD; however, these interventions are still under investigation (Mendell et al. 2021).

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1.4.2 Neurodevelopmental Disorders 1.4.2.1 Autism Spectrum Disorder The medications prescribed for ASD mainly treat self-injury, inability to focus, anxiety and depression (selective serotonin reuptake inhibitors (SSRI)), aggression (alpha-2 adrenergic agonist, Clonidine), and hyperactivity (dopamine and noradrenaline stimulant methylphenidate, Ritalin). For now, only two antipsychotics (risperidone and aripiprazole) are approved by the American Food and Drug Administration (FDA) for the treatment of some ASD symptoms, but newer strategies to treat core symptoms of ASD are directed to correct synaptic dysfunctions, abnormalities in central vasopressin, oxytocin and serotonin neurotransmission, and neuroinflammation. Besides the classical neurotransmitters, vasopressin and oxytocin provide neuropeptide targets for interventions. Although ASD can be a lifelong disorder, treatments and services can improve a person’s symptoms and daily functioning (László et al. 2023). 1.4.2.2 Schizophrenia In contrast to PD, in this case, dopamine hyperfunction might be the core problem; therefore, antipsychotics presumably antagonize the dopamine receptors. However, this can induce severe side effects (e.g., PD-like changes, hyperprolactinemia); therefore, newer drugs target other receptors as well, like serotonin (Zelena 2012). Electroconvulsive therapy is still in use for treatment-resistant cases. Moreover, supportive psychotherapy has the utmost importance not only for the affected individuals but also for the caregivers (Grover et al. 2017). 1.4.2.3 Attention-Deficit/Hyperactivity Disorder Paradoxically, ADHD is presumably treated with psychostimulants containing various forms of methylphenidate and amphetamine, increasing the monoamine (dopamine, noradrenaline) levels in the synaptic cleft. They have a calming effect on hyperactive children. FDA approved four non-stimulants for ADHD treatment: atomoxetine (glutamate receptor NMDA blocker), guanfacine and clonidine (both adrenergic alpha 2 agonists), and viloxazine (modulator of the serotoninergic system). Besides medication behavioral therapy is also recommended (Núñez-Jaramillo et al. 2021). 1.4.2.4 Tourette Syndrome Behavioral treatment, specifically cognitive behavioral intervention for tics, helps manage tics and enhances self-control (Robertson 2000). Medications like antipsychotics and alpha agonists help decrease tics. In severe circumstances, DBS can be useful via implanting electrodes to control aberrant brain activity (Schrock et al. 2015).

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1.4.3 Autoimmune Disease MS is an autoimmune illness and can be treated with disease-modifying medicines, including interferons, glatiramer acetate, and fingolimod, targeting immune response, delaying disease progression, and minimizing relapses. Corticosteroids are used during relapses to reduce inflammation. Symptomatic therapies include muscle relaxants and physical therapy to manage muscle spasms, while speech therapy addresses communication issues. Emerging immunomodulatory therapies hold promise for improved outcomes (Hauser and Cree 2020).

1.4.4 Prevalent Brain Disorders with Variable Origin 1.4.4.1 Stroke If a stroke occurs due to a blood clot, the clot-dissolving medicine Alteplase, if provided early, can enhance blood flow and limit harm. Thrombectomy involves mechanically removing blood clots to restore circulation. The emphasis is given to prevention, especially in risk populations with a constant usage of anticoagulants (e.g., nonsteroidal anti-inflammatory drug (NSAID), aspirin or K-vitamin antagonist Warfarin). Rehabilitation, comprising physical therapy, speech therapy, and occupational therapy, aids in recovery. Medications to address risk factors, such as antihypertensives and anticoagulants, prevent future strokes (Müller and Möhr 2019). 1.4.4.2 Epilepsy Antiepileptic medications, including phenytoin, carbamazepine, and valproate, are matched to seizure type and patient characteristics. The ketogenic diet, high in fat and low in carbohydrates, has demonstrated benefits in lowering seizure frequency. A possible surgical method is the vagus nerve stimulation, which involves implanting a device to stimulate the vagus nerve and may lower seizure severity. Other surgical approaches, such as resective surgery or responsive neurostimulation, might also be considered for drug-resistant cases (Liu et al. 2017). 1.4.4.3 Migraine NSAIDs, such as ibuprofen and acetaminophen, provide relief for mild attacks. Triptans like sumatriptan and rizatriptan target serotoninergic receptors and are useful in aborting mild to severe migraines. Beta-blockers propranolol and antidepressants SSRIs are used in the prevention of recurring migraines. Lifestyle adjustments, identifying triggers, and stress management approaches are crucial in preventing migraine attacks (Tfelt-Hansen 2021). 1.4.4.4 Neuropathy Neuropathy-induced pain is rarely sensitive to common NSAID painkillers. Usage of stronger opioid painkillers might lead to severe complications such as overdose, opioid diversion, and opioid-use disorder (Pohlmann et  al. 2009). Antiepileptic drugs gabapentin and pregabalin are the first-line agents in neuropathic pain. Their

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main target is a voltage-gated calcium channel (Kukkar et  al. 2013). Among the SSRI antidepressants, amitriptyline and duloxetine might help to treat neuropathic pain. Lifestyle adjustments, particularly blood sugar control for diabetic neuropathy, are critical. Physical therapy seeks to increase muscle strength and coordination (Cruccu 2007). So overall, the pharmacological treatment for neurological disorders has greatly advanced, bringing hope and an enhanced quality of life to patients. From disease-­ modifying medications to symptomatic therapy and their combination with psychoand behavioral therapy as well as specific surgical methods (e.g., DBS), these treatments address a wide range of neurological diseases. However, it’s vital to understand that individual reactions to treatments might differ, and current research continues to enhance these methods tailoring them to individual requirements and developing new ones.

1.4.5 Neuroinfectious Diseases The treatment of neuro-parasitic infections depends on the type of parasite that is causing the infection. Treatment for African trypanosomiasis includes drugs such as pentamidine, suramin, eflornithine, and nifurtimox. Cysticercosis is caused by the larvae of the tapeworm Taenia solium or Taenia crassicollis. Treatment for cysticercosis includes drugs such as albendazole and praziquantel. Treatment for echinococcosis often includes surgery to remove the cysts, as well as drugs such as albendazole (Jorgačevski and Potokar 2023). On the other hand, the treatment for malaria includes drugs such as chloroquine, quinine, and artemisinin-based combination therapies (Kamei 2021). Neurocysticercosis, which is caused by the larvae of the tapeworm Taenia solium, can be treated by drugs such as albendazole and praziquantel, as well as corticosteroids to reduce inflammation. Treatment for toxoplasmosis includes drugs such as pyrimethamine, sulfadiazine, and clindamycin. In some cases, surgery may also be necessary to treat neuro-parasitic infections (Danics et al. 2021). The treatment for brain diseases caused by bacteria, viruses, or fungi depends on the specific pathogen involved. However, some general principles apply to all types of brain infections. For example, antibiotics are effective against bacterial infections. They work by killing or inhibiting the growth of bacteria. The type of antibiotic used will depend on the type of bacteria that is causing the infection. Antibiotics are typically given intravenously (into a vein) for brain infections (Bowers and Mudrakola 2020). Antiviral drugs are effective against viral infections. They work by interfering with the replication of viruses. The type of antiviral drug used will depend on the type of virus that is causing the infection. Antiviral drugs are typically given orally (by mouth) for brain infections. Similarly, antifungal drugs are effective against fungal infections. They work by killing or inhibiting the growth of fungi. The type of antifungal drug used will depend on the type of fungus that is causing the infection. Antifungal drugs are typically given orally or intravenously for brain infections (Abraham 2013).

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In addition to specific treatment for the infection, supportive care is also important for people with brain infections. This may include pain relief, seizure control, management of fluid balance and electrolytes, nutritional support, etc. If you are concerned that you may have a brain infection, it is important to see a doctor right away. Early diagnosis and treatment can improve the chances of a good outcome.

1.5 Challenges Faced by Medical Professionals While Treating Neurological Disorders An early detection of neurological disorders is imperative for their proper treatment. Here are some of the common diagnosis methods for neurological disorders: (a) Medical history and physical examination: A detailed medical history, including family history and past medical conditions, along with a comprehensive physical examination, can often provide valuable clues to the underlying neurological condition. (b) Neurological examination: The neurologist assess the patient’s mental status, sensory functions, motor functions, reflexes, coordination, and balance to identify specific areas of the nervous system that are affected. (c) Imaging studies: Imaging techniques, such as CT scans, MRI scans, and PET scans, can provide detailed images of the brain and spine. These images can reveal abnormalities in structure, blood flow, and metabolism, which can aid in diagnosis. (d) Electrodiagnostic tests: Electrodiagnostic tests, such as EEG, electromyography (EMG), and nerve conduction studies, measure electrical activity in the brain, muscles, and nerves. These tests can help identify abnormalities in electrical signals, which can indicate damage or dysfunction in the nervous system. (e) Blood and cerebrospinal fluid (CSF) tests: Blood tests can detect abnormalities in blood cells, electrolytes, hormones, and other substances that may be associated with neurological disorders. CSF tests can analyze the composition of the fluid surrounding the brain and spinal cord to detect signs of inflammation, infection, or other abnormalities. (f) Genetic testing: Genetic testing can identify mutations in genes that cause neurological disorders. This information can be helpful in confirming a diagnosis, predicting the risk of developing the disorder, and making informed treatment decisions. (g) Neuropsychological testing: Neuropsychological testing assesses cognitive functions, such as memory, attention, and problem-solving. These tests can help identify cognitive impairments that may be associated with neurological disorders. (h) Biopsy: In some cases, a biopsy may be necessary to obtain a sample of tissue from the brain, spinal cord, or muscle for further examination. This can help confirm a diagnosis and provide information about the type and severity of the disorder.

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The specific diagnostic methods used will depend on the individual patient’s symptoms and medical history. The neurologist will carefully consider all the available information to get an accurate diagnosis. In spite of these diagnostic tools, neurological disorders represent unique and difficult challenges to medical professionals due to divergence (i.e., spectrum disorders) and convergence (i.e., similar symptoms due to diverse causes) in their symptomatology as well as due to heavy burden on the caregivers. From the gradual cognitive decline of AD to the terrible movement symptoms of PD, each disorder poses its own set of barriers that demand careful attention and knowledge. In this section, we highlight some of the primary problems clinicians confront in treating various common neurological illnesses and how they attempt to overcome them.

1.5.1 Neurodegenerative Disorders 1.5.1.1 Alzheimer’s Disease AD, a progressive neurological condition, presents clinicians with complex issues. Diagnosing AD in its early stages is challenging due to its gradual and insidious development. Distinguishing it from normal age-related cognitive decline requires comprehensive cognitive testing and neuroimaging (Vaz and Silvestre 2020). Additionally, AD lacks a definitive cure. Therefore, treatment plans may focus only on controlling symptoms and boosting quality of life. Clinicians must weigh the potential benefits of drugs like cholinesterase inhibitors and memantine with probable adverse effects and limited efficacy. The emotional toll on both patients and carers adds another dimension of difficulty. Addressing caregivers’ needs, providing support groups, and helping families through the progression of the disease require a holistic approach (Perneczky et al. 2023). 1.5.1.2 Parkinson’s Disease The difficulty in treating PD originate from its progressive nature and various symptoms. Developing a personalized treatment plan requires continuous monitoring and adaptation to the disease development (Sleigh et al. 2019). Levodopa, a cornerstone of treatment, sometimes leads to motor fluctuations and dyskinesias over time. Clinicians must find a fine balance between managing symptoms successfully and reducing medication-related problems (Shastry 2003). DBS brings its own set of issues. While highly beneficial for many patients, the selection process for potential candidates and the surgical procedure’s intricacy necessitates specialist knowledge. Adjusting stimulation levels and maximizing outcomes require continual coordination between neurologists, neurosurgeons, patients, and caregivers (Müller and Möhr 2019).

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1.5.1.3 Huntington’s Disease Its genetic underpinnings require the treatment of the whole family, including even distant relatives. Addressing chorea, cognitive impairment, and psychiatric problems demands a personalized therapy plan. The emotional issues of possible inheritance faced by patients and their families add to the complexity. Clinicians must provide psychological support, advice, and access to support groups to negotiate the emotional toll of the disease (Wyant et al. 2017). 1.5.1.4 Motor Neuron Diseases ALS, a rapidly progressive motor neuron disease, offers a unique set of issues for physicians. An early and precise diagnosis is vital due to the aggressive nature of the disease. The two approved therapies offer only moderate advantages and must be carefully assessed in terms of possible benefits and dangers. Addressing communication problems, dietary support, respiratory management, and emotional well-­ being necessitates a multidisciplinary approach combining neurologists, pulmonologists, speech therapists, and mental health practitioners (Priyadarshini and Ajroud-Driss 2023). On the other hand, although SMA now has curative treatment, one single injection costs over 1.5 million USD. Moreover, gene therapies are rather new. Therefore, medical professionals also must deal with the fear of the unknown.

1.5.2 Neurodevelopmental Disorders 1.5.2.1 Autism Spectrum Disorder Due to increased attention ASD is often over diagnosed, and placing pretty much normal children in a community with special educational needs often hinders their development. Moreover, due to a report in 1998 published in the Lancet, which suspected vaccination as a cause of ASD, the willingness to vaccinate has greatly decreased worldwide. Although several later reports, including more than 23 million children, discredited this article, the potential harmfulness of vaccines still lives in the public mind. This case highlights the great responsibility of researchers in shaping public opinion. 1.5.2.2 Schizophrenia The patients often lack disease awareness, and their hallucinations might make them suspicious of their environment. As SCZ is often accompanied by enhanced creativity, one might even think that treatment is not necessary. Therefore, establishing a good relationship with the patients and families is the first challenging step. Moreover, SCZ patients might be normal between episodes, which might deeply hinder the diagnosis. 1.5.2.3 Attention-Deficit/Hyperactivity Disorder The stream of information that surrounds us today demands our attention at every moment. It is not easy even for a normal person to focus. Therefore, the diagnosis

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of ADHD is also difficult because there is no sharp boundary between normal and pathological conditions. These days, this diagnosis is given quite often to children who are even slightly more lively, but sedating and calming the children does not serve their development and does not replace parental attention. Even in this case, the whole family would need to be treated.

1.5.2.4 Tourette Syndrome Distinguishing it from other movement disorders and addressing the considerable diversity in tic severity is critical for successful management. Behavioral therapy, a fundamental treatment, involves significant patient engagement and commitment. Achieving lasting improvement in tic control needs continual work from both the patient and the clinician (Chavhan et al. 2023).

1.5.3 Autoimmune Disorders: Multiple Sclerosis MS is distinguished by its unexpected course and wide-ranging symptoms. Clinicians must address the different requirements of patients, which can include treating relapses, decreasing disease progression, and reducing symptoms (Thakur et  al. 2016). Selecting the most appropriate disease-modifying therapy for each patient’s particular circumstances involves a thorough understanding of available drugs, their processes, and potential side effects (Sleigh et al. 2019). The problem in managing MS extends to emotional well-being. The chronic and unpredictable nature of the condition can contribute to worry and sadness among patients. Clinicians must be alert to these psychological components and incorporate comprehensive care into their treatment strategies (Valenzuela et al. 2011).

1.5.4 Prevalent Brain Disorders with Variable Origin 1.5.4.1 Stroke Stroke treatment issues entail the requirement for rapid intervention and complete rehabilitation. Administering clot-dissolving drugs within a tight window demands prompt and accurate diagnosis. Thrombectomy techniques demand a precise balance between intervention time and limiting consequences. The long-term challenges are recovery and preventing secondary strokes. Tailoring rehabilitation programs to individual needs and addressing risk factors require a multidisciplinary approach (Amorín et al. 2023). 1.5.4.2 Epilepsy Accurate diagnosis frequently needs a combination of clinical examination, EEG, and neuroimaging. Selecting the correct antiepileptic medicines demands examining seizure type, potential drug interactions, and specific patient characteristics. Clinicians have the issue of addressing treatment-resistant epilepsy disorders. While surgical techniques like resective surgery and responsive neurostimulation provide

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promise, finding potential candidates and managing the delicate surgical process is hard (Wu et al. 2023).

1.5.4.3 Migraine Migraine treatment problems emerge from the heterogeneity of symptom severity and causes. Developing effective preventive interventions entails understanding triggers and lifestyle adjustments. However, individual responses to drugs and lifestyle changes can differ dramatically. Managing acute attacks is equally challenging. While pain medications and triptans give comfort to some, choosing the proper medicine and dose regimen involves a trial-and-error approach (Lee et al. 2023). 1.5.4.4 Neuropathy Clinicians treating neuropathy must address the multiplicity of underlying causes, from diabetes to autoimmune illnesses (Cruccu 2007). Diagnosing the precise form of neuropathy requires careful clinical examinations and typically costly diagnostic procedures. Treating neuropathic pain offers complications due to varied reactions to treatments and potential side effects. Developing tailored pain treatment regimens entails evaluating each patient’s unique circumstances and preferences (Ismail 2023). Basically, treating neurological disorders  is a difficult enterprise that involves doctors negotiating sophisticated diagnostic processes, examining multifaceted treatment options, and addressing the psychological and emotional impact on patients and carers. A multidisciplinary approach combining neurologists, neurosurgeons, therapists, psychologists, and other professionals is typically necessary for delivering comprehensive care. Despite the hurdles, clinicians’ drive to develop their knowledge remains informed of the latest results of research, and personalizing treatments to specific patients holds the possibility of improving outcomes and improving the lives of those affected by these conditions. Personalized treatment, also known as precision medicine, is an approach to healthcare that tailors treatments to each individual patient’s unique genetic, molecular, and clinical characteristics. This approach has the potential to revolutionize the treatment of neurological disorders, which are often complex and difficult to treat. These are the following ways in which personalized treatment can be applied to neurological disorders: (a) Genetic testing: Genetic testing can identify mutations in genes that increase the risk of developing a neurological disorder or that affect the response to treatment. This information can be used to guide treatment decisions and to develop personalized treatment plans. (b) Biomarkers: Biomarkers are substances or molecules that can be measured in the blood, urine, or CSF to indicate the presence of a disease or to monitor the response to treatment. Biomarkers can be used to personalize treatment by identifying patients who are likely to benefit from a particular treatment or by monitoring the effectiveness of treatment.

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(c) Imaging studies: Imaging studies, such as MRI and PET scans, can be used to identify specific abnormalities in the brain or spinal cord that may be causing a patient’s symptoms. This information can be used to guide treatment decisions and to monitor the response to treatment. (d) Clinical data: Clinical data, such as a patient’s medical history, symptoms, and physical examination findings, can also be used to personalize treatment. This information can help to identify patients who are at high risk of developing complications or who may have difficulty tolerating certain treatments. By using a combination of these approaches, it is possible to develop personalized treatment plans that are tailored to each individual patient’s unique needs. This can lead to more effective treatments, fewer side effects, and improved patient outcomes.

1.6 Conclusion Neurological disorders are complex and may implicate the whole body. The divergence and convergence of their symptomatology may pose a diagnostic challenge. Presently, mostly disease-modifying treatments are available; however, newer therapies (e.g., DBS, ASO, AAVs) might also be curative. Nevertheless, the transdisciplinary approaches including surgeons, psychiatrists, psychologists, and other medical disciplines as well as the involvement of social workers and family members are also essential for the proper quality of life and well-being of our patients, which is challenging.

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Rise of Nanotechnology for Neurological Disorders Management Harshit Saxena, Akhilesh Kumar, Pooja Solanki, and K. Gowtham Bhandari

Abstract

Unveiling underlying pathological mechanisms and the development of improved diagnostic and therapeutic modalities are the main arenas of clinical research and development. When it comes to neurological disorders, the highly complex and self-contained organization of the nervous system makes the window of intervention arduous and limiting. Blood-brain, blood-spinal, and blood-nerve barriers, though being the formidable checkpoints for the various insults that can hamper the normal functioning of the nervous system, actually offer an impediment to pharmaceutical entities that can otherwise be obliged as important therapeutic and diagnostic options. Nanoscience has made a celebrated contribution to the field of neuro-theranostics in recent decades due to the exceptional chemical, electrical, optical, biological, and magnetic properties of nanomaterials. Nanomaterials proved to be highly efficacious in bypassing the barriers of the nervous system that are otherwise impossible to be traversed. Customizing nanomaterials with important pharmaceutical and diagnostic agents for specialized delivery to nervous tissue has made neuro-nanotechnology a paradigm approach in neuromedicine. Keywords

Neuro-nanotechnology · Neurological disorders · Nanomaterials · Neuroimaging · Neurotherapeutics · Blood-brain barrier

H. Saxena (*) · A. Kumar · P. Solanki Division of Medicine, ICAR-IVRI, Izatnagar, Bareilly, India K. Gowtham Bhandari Department of Pharmacology, KLE College of Pharmacy, Bangalore, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_2

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2.1 Introduction The term “neurological disorders” pertains to illnesses of the central and peripheral nervous systems, affecting various discrete regions (Ghosh et al. 2021). Neurological illnesses like Alzheimer’s disease, dementia, Parkinson’s disease, depression, obsessive-compulsive disorder, multiple sclerosis, epilepsy, migraine, benign and malignant tumors, and stroke, along with infectious neurological diseases, pose a significant burden on global health. The progression of the neurological disorder showed worrisome perspectives as the healthcare resources are overstretched (Feigin and Vos 2019). In 2019, during pre-pandemic times, neurological disorders stood at 970 million, and in the post-pandemic era of 2020, there was an exponential rise in neurological disorders. The estimates in GBD 2019 stated people living with neuropsychiatry, neurodevelopmental, and neurocognitive disorders also affected the normal life of the population (WHO 2022). The understanding of various neurological illnesses or pathophysiological processes has greatly benefited and has been altered at times by the rising amount of neurological research. Some contributions concentrate on diseases with a smaller geographic scope, but they nonetheless provide breakthroughs that may be built upon in subsequent studies (Mbewe et  al. 2013; Birbeck et  al. 2015; Nair et  al. 2012). Our understanding of the underlying pathophysiology appears to be sufficient for the creation of innovative therapeutics, but outcomes are unsatisfactory when new medications are tested to treat the patients. Current medical therapies with advanced treatment modalities, although they increase the survival period, are insufficient for a complete cure of neurological diseases impacting life significantly (Nguyen et al. 2021). The existence of crucial intervention windows for brain development raises the possibility that early treatments may be required to address deficiencies that arise later as a result of previous disturbances. It creates room for an advanced approach to the development of therapies essential to surpass the intervention window and impart long-lasting beneficial effects, underscoring the importance of developing novel therapeutics (Marín 2016). The notion of nanotechnology was first introduced in 1959 by the physicist Richard Feynman. Nanoscience focuses on the sub-100 nm range. Nanotechnology is the scientific field of focusing on creating structures or useful materials at the nanoscale using both physical and chemical techniques (Anjum et al. 2021). Since nanotechnologies provide better-built, cleaner, enduring, and more competent goods, they have had a substantial influence on practically all sectors and areas of society. Nanotechnologies have transformed medical advancements, particularly in diagnostic procedures, imaging, and medication administration. These have been employed in the personalization of medicine, accurate and precise medication delivery systems, automatic and robotic surgical methods, and retinal implants and cochlear implants having the capacity to reattach damaged nerves (Sim and Wong 2021). Numerous nanoparticles have been used in neurological studies and research, opening new doors for biomedical science thanks to nanotechnology (Waris et al. 2022). Nanoparticles [NPs] are ultrafine particles used to develop innovative

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treatment techniques effectively and precisely (Teleanu et  al. 2019). To break through the BBB, NPs employ both organic (PLA, PLGA, and trehalose) and inorganic elements (silica, molybdenum, cerium, iron, and gold) as a core (Fig.  2.1) (Anjum et al. 2021). Researchers are curious to investigate the predicted interventional strategy in the distinct fields of medicine that will cure neurologic illnesses, cancer, and tissue regeneration due to the specificity and targeting of NP in complex biological systems (Freitas Jr. 2005; Shabani et al. 2023). A few nanoparticles and nanomaterials have so far undergone research and received clinical use approval. Table 2.1 discusses several typical forms of nanomaterials (Sim and Wong 2021). Neuro-nanotechnology is an integration of two distinct fields of neuroscience and nanotechnology, which address the issues of neurological disorders (Chaudhary 2022). This multitude of nano modalities has contributed to neurobiology in designing nanomaterials/nanoformulations (Bhattacharya et  al. 2022; Pampaloni et  al. 2019). The evolving possibilities have advanced the use of NPs in the diagnosis by

Fig. 2.1  Various polymers used in the nanofabrication of drugs (Nguyen et al. 2021)

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Table 2.1  Nanomaterials in neurological disorders Nanoparticles Carbon nanotubes and fullerenes

Dendrimers

Micelles

Nano emulsions

Polymeric NPs

Solid lipid nanoparticles

Description These carbon allotropes stand out for their outstanding thermal, electrical, and mechanical capabilities as well as their hollow structure (Anjum et al. 2021) The three-dimensional symmetrical structure of dendrimers includes an inner multi-hyperbranched core, including functional groups at the terminal surface that may be conveniently integrated with several ligands (Anjum et al. 2021) Micelles are vesicles with an exterior hydrophilic segment and an interior hydrophobic core that can be formed via amphiphilic surfactants or amphiphilic copolymers (Anjum et al. 2021) Edible oils, surfactants, and water are combined to form nano emulsions, which may or may not contain colloidal particulates (Anjum et al. 2021) These are the solid colloidal dispersion of biocompatible, biodegradable polymers with a dense polymer core and a hydrophilic outer layer to offer steric stability (Anjum et al. 2021) They consist of a lipid-based aqueous colloidal nano-carrier system that is added to water or a surfactant solution, and typically solidify when cooled (Anjum et al. 2021)

Uses This was efficiently used in neurodegenerative diseases like Alzheimer’s and Parkinson’s (Anjum et al. 2021; Mbewe et al. 2013) The system is efficient in drug delivery due to its hydrophilic and hydrophobic nature (Anjum et al. 2021; Md et al. 2014; Misra et al. 2016)

This system helps in the delivery of hydrophobic drugs to the CNS (Anjum et al. 2021; Mohamadpour et al. 2020)

This efficiently surpasses the BBB, thus resulting in the rapid distribution of drugs (Anjum et al. 2021; Nair et al. 2012) The lipophilic drugs can be attached to the surface by means of encapsulation, which provides steric stability and drug targeting (Anjum et al. 2021; Naqvi et al. 2020) The nanocarrier system consists of aqueous colloids and lipids to load drugs and have better therapeutic action, for example, quercetin loaded to treat AD (Anjum et al. 2021; Negro et al. 2017)

means of labeling with the objective of optical imaging, accurately visualizing the internal structure(s) (Kumar et  al. 2017) and real-time imaging, which improves both anatomic and functional visualization (Tan et al. 2017). In neurosurgery, the approach is a very extensive and skill-aided job. The nanoscience approach led to the development of nano-engineered bots, which aid in providing external control for implanting the biomaterials or targeting the drugs at a specific site with minimal invasion to the system (Tan et al. 2017). The created nanostructure has the potential to be used in neurological research (Shabani et al. 2023). NPs are developed from synthetic, organic, and metallic nanostructures and thus are implicated in cutting-­ edge ND therapies (Lang et al. 2018).

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The use of NPs for drug delivery across the blood-brain/spinal/neural barrier is the ice-breaking technology of this era, which is capable of transpiring miracles in achieving victory over neurological illnesses. Data from several research using customized NPs have widely disseminated their compatibility and more effectively focused on discrete site action. In addition, it also exhibits high efficiency in the targeting ability and consequently advances their efficacy. Customized NPs specialized for neuronal delivery are thrust in present-day research. In research utilizing PLGA NPs, the mitoNEEt ligand inhibitor NL-1 was successfully targeted in a brain ischemia/reperfusion model without causing any harm (Ngowi et  al. 2021; Saralkar et  al. 2020). Studies on neuroimaging, ND pathologies, biomarker detection, drug delivery, irradiation, and radiosensitization in neurological illnesses provided proof of the therapeutic effectiveness of nano neurotechnology. Currently, almost 250 NPs have been authorized by the US FDA for use in the treatment of meningitis, multiple sclerosis, schizophrenia, and epilepsy, thus improving the quality of treatment (Ngowi et al. 2021; Ventola 2017). Though nanomaterials come with an array of benefits, they must be handled carefully in biological systems because of their highly bio-reactive nature that possesses both fair and dark sides in the living system (Chaudhary et al. 2023).

2.2 Prerequisites of Designing Nanoparticles for Nervous Disorders Entry of nanoparticles through the blood-brain/spinal/nerve barrier is mainly attributed to the mechanism of transcytosis, which can be adsorptive or receptor-­mediated. However, the mechanism of transcytosis begins with endocytosis and is facilitated through either clathrin or caveolin-enriched areas of the nervous system (Ceña and Játiva 2018). This passage of nanoparticles further depends on characteristics like size, charge, and surface chemistry of nanoparticles. Size range of less than 100 nm, positive surface charge, and modification of the surface with legends for various targets like Lf receptors, GLUT1 or albumin transporters, LRP1 (targeted by angiopep-­2) or Tf receptors are favorable characteristics of a nanoparticle designed for drug delivery to the nervous system (Ceña and Játiva 2018). These characteristics of NPs offer a promising approach to targeting the brain’s discrete regions more efficiently to circumvent the diagnostic and therapeutic process.

2.3 Nanotechnology in the Diagnosis of Neurological Disorders Diagnostic algorithm of neurological disorders starts from a multitude of clinical signs that the patient experiences to several laboratory-based assays and imaging techniques that give clues about functional, biochemical, and structural aspects of the nervous system (Jankovic et al. 2022). Research in biochemistry and medicine frequently uses imaging techniques, including X-rays, ultrasounds, computed

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tomography, nuclear medicine, and magnetic resonance imaging (Gautam 2022). However, they are able to evaluate alterations on the tissue surface relatively late in the progression of the disease; these methods can be enhanced by the use of contrast and targeting agents utilizing nanotechnologies to improve resolution and specificity by highlighting the diseased site at the tissue level (Sim and Wong 2021). Nanomaterials have found application in the designing of biosensors for the detection of several biomarkers and real-time imaging of nervous tissue for the diagnosis of an ailment (Shabani et al. 2023). Nanomaterial-based sensors like that for acetylcholine estimation that detects pH change on Ach hydrolysis, gold nanoparticle/ quantum dots-based biosensors for detection of glutathione, DNA/SWCNT-based surface immobilized biosensors for detection of Dopamine, nanoribbon field-effect transistors (FETs) of In2O3 for detection of serotonin/dopamine, and many more have created a revolution in making the estimation process of these neurotransmitters and biomarkers easier (Kanwar et  al. 2012). As far as neuroimaging is concerned, nanotechnology is exhaustively used to modify and enhance attributes of already available options of imaging. Iron nanoparticles like super magnetic iron oxide (SPIOs), ultrasmall super magnetic iron oxide (USPIOs) nanoparticles, very small super magnetic iron oxide nanoparticles (VSPIOs), and their modified forms like Ferumostran-10, Ferumoxides, and Ferumoxytol have been used as a contrast agent in MRI and is proved to provide better visualization of tumors and ischemic areas when given intravenously compared to conventional gadolinium (Suffredini et al. 2014). Quantum dots have also been proved for early visualization of tumor cells in the brain, and their modified forms like tagging with membrane translocation peptide (TAT), encapsulated quantum dots in polyethylene glycol and poly lactic acid, have made them traverse the BBB barrier and administer via nasal route directly to brain respectively where they can assist microangiography of vessels of the brain (Utkin 2018). Nanowires made from platinum have been implied to directly read electric signals from the brain without directly traversing the skull and brain but as catheters placed through major blood vessels and guided to the brain (Vidu et al. 2014). Electrodes coated with multi-walled carbon nanotubes have been used in electroencephalography to get better signals and reduce noise (Komane et al. 2016).

2.4 Nanotechnology in the Treatment of Neurological Disorders The current medical treatment options available for neurological disorders may increase survival, but they are insufficient to treat NDs, which significantly impact the quality of life and pose challenges to the healthcare systems (Feng et al. 2020). Even though development is a continuous process, there is evidence that the brain is particularly susceptible to insults [both genetic and environmental] during certain, vulnerable stages where changes in the brain and its intricate blood-brain barrier (BBB) structure have a long-lasting effect across the lifespan (Hübener and Bonhoeffer 2014). In addition to the crucial intervention window, the BBB filters a

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lot of medications that make the intervention ineffective. To increase the potency of the available drugs for treating CNS disorders, nanomedicine-based therapeutic systems are used, which represent a new way to deliver useful pharmaceutical compounds with promising pharmacokinetics (Table 2.2). Several nanomaterials have been used as nanomedicines to deliver various drugs to the targeting sites (Liu et al. 2020). In order to treat Alzheimer’s disease, various nanocarriers are being used, including chitosan nanofiber (AnjiReddy and Karpagam 2017), poly[lactic-co-glycolic acid] NPs (Md et al. 2014), ApoE3-conjugated polymeric NPs (Krishna et al. 2019), Novel-L lactide polymeric NP, chitosan NP (Pagar et  al. 2014), methoxy poly[ethylene glycol]-co-Poly[ε-caprolactone] NPs (Mohamadpour et  al. 2020), thiolated chitosan NPs (Sunena et  al. 2019), solid lipid NPs (Misra et  al. 2016), PLGA-NPs with Tween 80 coated (Mittal et  al. 2011), polysorbate 80-coated poly[n-butylcyanoacrylate] nanoparticles (Wilson et al. 2008), while others, such as chitosan-coated nanoliposomes (Cao et  al. 2016), poly[l-DOPA]-based self-­ assembled nanodrug [NanoDOPA] (Vong et al. 2020), Rotigotine-loaded chitosan nanoparticles [RNPs] (Bhattamisra et  al. 2020) and PLGA Microspheres (Negro Table 2.2  Nanopharmaceuticals used in treating various CNS disorders NPs Dendrimers

Polymer NP (PEGylated IFN-β-1a) Polymer NP Iron oxide NPs Chitosan nanofiber

Route of administration Oral, topical, transdermal, intravenous Subcutaneous injection Subcutaneous injection Intravenous Oral

Disease condition Psychotic disorders

Reference Saeedi et al. (2019)

Multiple sclerosis

Nguyen et al. (2021)

Alzheimer’s disease

AnjiReddy and Karpagam (2017) Krishna et al. (2019) Fazil et al. (2012) Misra et al. (2016) Wilson et al. (2008) Cao et al. (2016)

ApoE3 conjugated polymeric NPs Chitosan NP Solid lipid NPs Polysorbate 80-coated poly(n-butylcyanoacrylate) NPs Chitosan-coated nanoliposomes

Oral

Poly(l-DOPA)-based selfassembled nanodrug (NanoDOPA) Rotigotine-loaded chitosan nanoparticles (RNPs) ss Echogenic liposomes

Intraperitoneal

Vong et al. (2020)

Intranasal

Bhattamisra et al. (2020) Laing et al. (2012)

Antioxidant-loaded PLGA NPs

Catheterization

Intranasal Intravenous Intravenous Intragastric

Intra-arterial sheath

Parkinson’s disease

Ischemic stroke

Petro et al. (2016)

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et al. 2017) used to deliver drugs like Levadopa, poly[l-DOPA[OAc]2], the precursor of Levodopa, Rotigotine and Ropinirole, respectively, which utilized in the treatment of Parkinson’s disease. A proprietary nanomaterial containing echogenic liposomes (Laing et al. 2012) and antioxidant-loaded PLGA nanoparticles (Petro et al. 2016) are being used to achieve enhanced functional recovery after ischemic stroke and reperfusion injury through the intra-arterial sheath and catheterization route. In the clinical setting, nanomedicine such as Copaxone® [polymer nanoparticles], Plegridy® [Biogen] [PEGylated IFN-β-1] is used to treat multiple sclerosis, and DepoCyt® [Cytarabine encapsulated in multivesicular liposomes] is used to treat lymphomatous malignant meningitis. Several drugs have been tested in phase II trials, including 5-fluorouracil [5-fluorouracil-releasing microspheres], PEG-Dox [Pegylated liposomal DOX], SGT-53 [SynerGene Therapeutics] [cationic liposome with anti-transferrin antibody] to treat glioblastoma multiforme and ferumoxytol [iron oxide nanoparticles] for brain neoplasms and AGuIX [Polysiloxane gadolinium-­chelates based NPs] for brain metastases (Nguyen et al. 2021). The use of nanotechnology to deliver phytochemicals that possess immense benefit in the rejuvenation of body systems along with the nervous system has the capacity to revolutionize the herbal medicine approaches (Thukral et  al. 2023). Various types of plant-based medicines are used in the treatment of NDs along with conventional approaches, which include Acorus calamus, Allium sativum, Bacopa monnieri, Centella asiatica, Curcuma longa, Coriandrum sativum L., Galanthus nivalis, Ginkgo biloba, Glycyrrhiza glabra, Hypericum perforatum, Ocimum sanctum, Melissa officinalis, Rosmarinus officinalis, Salvia officinalis, and Withania somnifera (Bhattacharya et al. 2022).

2.5 Future Perspective of Nanotechnology in Neurological Disorders The nano-based approach has been innovative and shown promising strategy to aid in the improvement of illness detection and treatment (Ngowi et  al. 2021). The development of drug delivery using nanoparticles in the past few decades has shown an intriguing way for medications to diffuse through the BBB, permeate the CNS, and execute their intended activity (Waris et al. 2022). It is important for researchers to conduct exhaustive and holistic toxicological research on brain-targeting nanoformulations with established mechanisms of action and pharmacokinetics, both with and without medical interventions. The prevailing need for effective nano-­ based treatments focuses largely on neurological protection and regeneration, which would reap enormous rewards from advancing nano-based approaches (Naqvi et al. 2020). Nanotechnology’s ability to radically transform the approach for CNS-­ targeted treatments in the future is highly encouraging and offers new doors for the treatment of neurological illnesses (Ghosh et al. 2022).

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2.6 Conclusion The application of nanotechnology to deliver important pharmaceutical agents of interest for the diagnosis and therapeutic management of neurological diseases is revolutionary. Drugs/agents that were earlier forbidden for use in neurological disorders due to their inability to cross the blood-brain/spinal/nerve barrier can now be designed in nanoformulations for their delivery to nervous tissue. Several promising studies proved the worth of nanomaterials in uplifting the present healthcare system of neurodiagnostics and neurotherapeutics. However, the safety status of these must always be taken into consideration in order to prevent any insult to the biological system. Neuro-nanotechnology will grow with leaps and bounds in the coming years and will necessarily aid in improving the global scenario of world neural health.

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Implications of Nano-Biosensors in the Early Detection of Neuroparasitic Diseases Shabir Ahmad Rather, Rashaid Ali Mustafa, Mohammad Vikas Ashraf, M. A. Hannan Khan, Shoeb Ahmad, and Zahoor Ahmad Wani

Abstract

Parasitic diseases affecting millions of people globally cause fatalities and incapacitating conditions. It is, therefore, essential to detect parasitic diseases by looking for the parasite/s or their specific proteases that they produce at different phases of their life cycles. Numerous symptoms and indicators can result from a parasitic infection of the neurological system, but it is still challenging to diagnose an infection because the symptoms are frequently vague or minor. It is more likely that a parasite infection of the nervous system will be identified and treated well if one is familiar with fundamental epidemiological traits and distinctive radiography findings. For accurate diagnosis of these neurological disorders, proper identification and adoption of acceptable public health measures for the management of epidemic outbreaks are required. For numerous diseases, conventional in vitro techniques are time-consuming and need centralized facilities. So, the development of biosensor technology could lead to point-of-care diagnostics that are as accurate, fast, and affordable as or better than current standards. Modern biosensors include varied sensing techniques, such as optical, electrical, and mechanical transducers, as well as micro- and nanofabrication technologies. Only a handful of well-known biosensor examples have successS. A. Rather · R. A. Mustafa · M. A. Hannan Khan Department of Zoology, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, India M. V. Ashraf · S. Ahmad Department of Biotechnology, School of Biosciences and Biotechnology, Baba Ghulam Shah Badshah University, Rajouri, Jammu and Kashmir, India Z. A. Wani (*) Division of Veterinary Parasitology, SKUAST-K, Shuhama, Jammu and Kashmir, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_3

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fully transitioned from laboratory research to clinical applications despite the need for the medical community. Biosensor-based diagnosis of protozoan diseases like malaria, leishmaniasis, American trypanosomiasis (Chagas disease), and toxoplasmosis has been accomplished but is still in the infancy stage. In addition to the advancements in biosensors for the diagnosis of parasitic infections, we highlight the considerable challenges that must be overcome in order to bring integrated diagnostic biosensors into use in real-world scenarios. Keywords

Biosensors · Neurological diseases · Parasites · Diagnosis · Applications

3.1 Introduction Infections of the central nervous system (CNS) are crucial because they compromise central nervous system health (Sundaram et al. 2011). It has been estimated that 25% of people worldwide are parasite-infected, with infections being more common in developing rural areas and agriculture of subtropical and tropical countries (Youssef and Uga 2014). It’s possible for human parasites to live in the CNS or another unusual area of the body. Globally, CNS parasite infections are regarded as major causes of morbidity and mortality. There are several distinct species that can be categorized as parasites, including metazoans, which are multicellular organisms, and protozoa, which are single-celled organisms (Carpio et  al. 2016), which can be either free-living or obligatory in nature (Walker and Zunt 2005). The majority of eukaryotic cells on earth are protozoa, which are vital pathogens for humans as well as animals (Zarlenga and Trout 2004), where they can cause extremely minor to serious, lifethreatening illnesses Lim et al., 2016). Helminths wreak physical havoc on the tissues they inhabit, triggering a strong inflammatory reaction (Graeff-Teixeira et al. 2009). Humans are infected by a wide variety of parasites, and occasionally a substantial number of these parasites move to the central nervous system and cause illness (Nash 2014). Diseases caused by soil-transmitted helminths, Toxoplasma gondii, Schistosoma, Taenia solium, and Plasmodium can all result in neurological impairments (John et  al. 2015; Abdel Razek et al. 2011). Molecular recognition of a target analyte is converted into a quantifiable signal by a transducer in a biosensor. The glucose sensor, which was first introduced 30 years ago in its current form and is still in use today, is the most well-known example. It has completely changed how diabetes is managed. Assays using lateral flow, such as those used in home pregnancy tests, are other prevalent examples (Luong et al. 2008). Biosensors have the potential to provide a user-friendly, sensitive, and affordable technology platform for infectious disease diagnosis and therapy prediction (Foudeh et  al. 2012). Low energy consumption, short test times, multiplexing capability, and high portability are some benefits, including small fluid

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volume manipulation (cheaper cost and less reagent) (Whitesides 2006). Biosensors that can carry out the intricate molecular tests necessary for many infectious diseases have recently been developed as a result of recent advancements in micro- and nanotechnology. Parallel to this, important strides have been achieved in our understanding of pathogen genomes, proteomics, and interactions with the host (Mairiang et  al. 2013). While biosensor-based immunoassays may boost the sensitivity of pathogen-specific antigen detection, multiplex detection of host immune response antibodies (serology) may increase overall specificity. Additional system integration might make it easier to build assays that incorporate both pathogen-specific targets and indicators of host immune responses at various phases of infection (Mohan et al. 2011). The first-ever Global Neglected Tropical Disease Day was founded in 2020 (on January 30) to commemorate the recent advancements in the battle against diseases, to inspire businesses and nations to take action in remembrance of the challenges yet ahead, and to celebrate the achievements. Despite joint efforts to develop effective and safe treatments and remove vectors, precise and early identification is the initial action needed to speed up the therapy. Some diseases can be quickly identified through clinical evaluation or pattern recognition of the physical symptoms, while asymptomatic disorders and diseases that are just beginning to manifest are more challenging to identify. The most common course of action, utilizing knowledge of the pathogen genome and the host’s immunologic response, is a molecular and serological diagnosis using techniques like enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT PCR) (Lammie et al. 2011). The downsides of these and other tests include the need for high-quality personnel, pricey tools and chemicals, and time-consuming procedures along with inadequate infrastructure and resources. Furthermore, these tests continue to exhibit cross-reactivity, such as with the arboviruses, dengue, and Zika (Zaidi et al. 2020), as well as false-negative and false-positive results, as is seen in the case of SARSCoV-2 pandemic (Lorentzen et al. 2020). The creation of diagnostic systems that can identify diseases in their earliest stages with high specificity, cheap cost, sensitivity, and robustness while also being simple to use becomes of vital importance. These benefits of biosensors are in addition to the potential for the creation of miniature loco determination systems, which meet the needs of low-income nations and remote areas like conflict zones or native tribes. With an emphasis on the differences between various signal transducer techniques and their potential for clinical translation, this chapter focuses on developments in biosensor technology for neuro-parasitic disorders. Labelled and label-free assays are the two types of detection techniques, among which label-free assays directly detect the presence of an analyte through biochemical processes on a transducer surface (Rapp et al. 2010). A biosensor is a sensing device or a measurement system that is specially created for the estimation of a substance using biological interactions and then interprets these interactions into a readable form using transduction and electromechanical methods (Chaudhary et al. 2023). Figure 3.1 gives us information about the three

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Fig. 3.1  Block diagram of biosensor

main components of a biosensor. These parts are the bioreceptor, the transducer, and the detector in terms of the conceptual and fundamental manner of functioning. A biosensor’s primary job or objective is to detect a substance with a biologically specified composition. These substances frequently consist of proteins, immunological compounds, antibodies, enzymes, etc. It is accomplished by utilizing a different physiologically delicate substance that contributes to the creation of the bioreceptor. In other words, a bioreceptor is the part of a biosensor that acts as a template for the substance to be detected. Bioreceptors can be made from a variety of materials. For instance, a protein is screened using its equivalent selective substrate, while an antibody is screened using antigen and vice versa. The transducer system is the second element. This device’s primary job is to electrically represent the interaction between a bioanalyte and the appropriate bioreceptor. “Trans” signifies change, and “ducer” implies energy, according to the name itself. Transducers, then, essentially change one kind of energy into another. The first form, which is produced by a particular interaction between the bioanalyte and bioreceptor, is biochemical in nature, whereas the second form is typically electrical in character. Transducers are used to convert the biological response into an electrical signal. The detection system is the third element. It does this by receiving the electrical signal from the transducer component and amplifying it appropriately so that the related response can be correctly read and analyzed. The availability of immobilization schemes that may be utilized to immobilize the bioreceptor in order to increase the feasibility and efficiency of its reaction with the bioanalyte is a crucial necessity for nano-biosensors in addition to these components. The performance of the systems based on this technique is also impacted by changes in temperature, pH, interference with pollutants, and other physicochemical fluctuations, which makes immobilization the overall process of biological sensing more affordable (Kissinger 2005). In essence, nano-biosensors are nanomaterial-based sensors that are interestingly not specialized sensors that can detect tiny events and occurring (Gautam 2022). Nanomaterials, or materials with one of their dimensions between 1 and 100 nm, are a special gift that nanotechnology has given to humanity. These materials are

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extremely unique due to their size limitations. They differ greatly from the same materials at the bulk scale in all significant physicochemical aspects and have the majority of their constituent atoms localized at or near their surface. They can perform extremely effective functions in the biosensor technology’s sensing mechanism. Nanoelectromechanical systems (NEMS), which are highly active in their electrical transduction mechanisms, are created when devices made of nanomaterials are integrated with electrical systems. On the basis of their electrical and mechanical characteristics, a number of nanomaterials have been investigated for use in enhanced biological signaling and transduction pathways. Nanowires, nanotubes, nanoparticles, thin films, and nanorods comprised of nanocrystalline matter are a few examples of these materials that are frequently used (Jianrong et al. 2004). Among these, the usage of nanoparticles has received the most attention and analysis to date. The miracles of nanotechnological implications of the matter have made it feasible for nano-biosensors to play a very important role in the development of biosensor technology (Chaudhary 2022). Numerous studies throughout the world have looked into a wide range of biosensing tools that use nanoparticles or nanostructures. These can range from employing amperometric tools for the enzyme-based detection of glucose to using quantum dots as fluorescent agents for the binding detection to even using bioconjugated nanomaterials for targeted biomolecular detection. For use in immunosensing and immunolabelling, they include colloidal nanoparticles that can bind to antibodies. These components can also be employed to improve electron microscopy-based detections. Additionally, metal-based nanoparticles are particularly good materials for electronic and optical applications. By utilizing their optoelectronic capabilities, these nanoparticles can be effectively exploited for the detection of nucleic acid sequences. The primary categories of nanomaterials used to improve upon the sensing mechanisms now in use in biosensor technology are listed in Table 3.1. It emphasizes the potential benefits of a number of nanomaterials used and some proof of their use thus far.

Table 3.1  An overview of nanomaterial used for improving biosensor technology Nanomaterial used Nanoparticles Nanorods

Carbon nanotubes Nanowires Quantum dots

Benefits Aid in immobilization, enable better loading of bioanalyte, and also possess good catalytic properties Good plasmonic materials which can couple sensing phenomenon well and size-tunable energy regulation, can be coupled with MEMS, and induce specific field responses Improved enzyme loading, higher aspect ratios, ability to be functionalized, and better electrical communication Highly versatile, good electrical and sensing properties for bio- and chemical sensing; charge conduction is better Excellent fluorescence, quantum confinement of charge carriers, and size-tunable band energy

References Luo et al. (2006) Kabashin et al. (2009) Davis et al. (2003) MacKenzie et al. (2009) Huang et al. (2005)

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In keeping with this theme, carbon nanotubes have also been employed to enhance biosensing processes through their capacity to enable quick detection and much-improved interactions between the analyte and the bioreceptor molecule. For the detection of glucose (Chen et  al. 2008) and insulin (Qu et  al. 2006), carbon nanotube-based biosensors have been in use. The text that follows discusses the benefits and results of using various nanomaterials, as well as their inherent advantages and the crucial factors that can greatly affect their effectiveness.

3.2 Echinococcosis (Hydatid Disease) Echinococcus granulosus and Echinococcus multilocularis are the two cestode species that infect humans most frequently (Algros et al. 2003). Cystic hydatid disease caused by endemic parasite E. granulosis is more frequently occurring in Latin America, the Middle East, and the Mediterranean region (Al zain et  al. 2002). Alveolar echinococcosis (also known as alveolar hydatid disease) that is native to China, Turkey, Alaska, and central Europe is caused by E. multilocularis. The parasite can infect household dogs and cats, although its primary hosts are red and Arctic foxes. According to epidemiological evidence, rodents and dogs or foxes can transmit the E. multilocularis to each other as they come into contact with infected animals. More frequently, females and children suffer disproportionately in endemic nations (Kern et al. 2003). Canids like dogs and wolves have E. granulosus adults in their intestines (Bouree 2001). Following ingestion of egg by ungulates, the oncospheres swiftly move from the small intestine to the liver before moving by lymphatic vessels or blood to the lung, kidney, pericardium, vertebrae, periorbital tissue, and brain, where it develops into hydatid cyst. Hydatid cysts, which are filled with a serous fluid containing scolices, also develop in infected humans (Garret et al. 1977). Solitary hydatid cysts form in the liver as a result of the majority of infections. However, unlike E. granulosus, E. multilocularis mostly affects the liver. It can also spread by blood or lymphatic channels to other organs. Hydatid cysts are usually taken up by canids along with infected offals, where multiple scolices get released, and they penetrate deeply between villi into the crypts of Liberkuhn and develop to maturity in about 47 days. Echinococcosis patients frequently have elevated erythrocyte sedimentation rate (ESR) and serum eosinophilia. Eosinophilia in the cerebrospinal fluid (CSF) is normally absent because echinococcal infections are encapsulated. A veterinarian ought to be consulted when echinococcal infection in humans is identified because farm animals or domestic pets, particularly dogs, are frequently the source of the infection. Serum indirect hemagglutination (IHA), indirect fluorescent antibody (IFA), and enzyme-linked immunosorbent assay (ELISA) can all be used to confirm the diagnosis of E. granulosus infection, approximately 98% for patients with hepatic cysts, while the test sensitivity values range from 50% to 60% in patients with pulmonary cysts. Serum assays to identify E. multilocularis are more accurate and non-cross-reactive than those to identify E. granulosus (Jiang et al. 2001). A negative antibody detection test does not rule out the diagnosis of Echinococcosis

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because some cyst carriers do not produce detectable antibody levels. Serological testing is not advised as a way to gauge treatment effectiveness because it cannot predict CNS involvement (Gottstein 1992).

3.2.1 Biosensor Application for Diagnosis of Echinococcosis A dreadful parasitic disease that affects millions of people worldwide is echinococcosis and has had disastrous impacts on animal husbandry because it has been neglected. Recent studies have focused on a number of characteristics of E. granulosus, including its global distribution, pathology, diagnostic techniques, and innovative therapeutics for both humans and animals (Wen et  al. 2019; Eckert and Thompson 2017). Despite the fact that this zoonotic parasite can be diagnosed in a number of ways, many of these tests are expensive, complicated, and call for specialized training. The imaging techniques, like ultrasonography and radiography (X-ray), are among the popular methods used to screen the population at a fair price (Wen et al. 2019). According to McManus et al. (2012) and Gottstein et al. (2014), serology tests are also frequently used to identify indicators from the host (markers of inflammation, cytokines, or chemokines) and parasite (circulating antigens or DNA). For the diagnosis and management of echinococcosis, practitioners can now adhere to precise manuals and algorithms (Wen et al. 2019; Brunetti et al. 2010). Cystic echinococcosis (CE) is diagnosed in the lab using a variety of substances, including antibodies, antigens, and cytokines. The lack of sensitivity and/or insufficient specificity of these methods, however, make them unsuitable as reliable diagnostic tools (Siles-Lucas et  al. 2017). Furthermore, they call for particular infrastructure configurations and qualified employees. Due to the advancement of nanotechnology, the creation of biosensors for the diagnosis of echinococcosis has currently achieved significant advancements. Using the near-infrared transmission angular spectra of porous silicon microcavities, an efficient method for an optical biosensor for the diagnosis of cystic hydatid disease was developed by Li et al. in 2017. A more recent study (Darabi et al. 2019) found that in silico design and evaluation was an effective way to identify the antigens present in hydatid cysts. To swiftly, precisely, and effectively detect parasites, viruses, etc., researchers have been creating portable electroanalytical biosensing equipment or analyzers. More straightforward and quick methods are still desperately needed despite recent significant advancements. Because of their mechanical and chemical characteristics, which are useful in both veterinary and human health, nanoparticle-based biosensors are greatly desired (Cesewski and Johnson 2020; Moulick et al. 2017). The use of nanometal products has brought attention to the need for efficient parasite management techniques, but the nanoparticles will likely contaminate the environment (Lin et al. 2010), necessitating the establishment of safe use procedures and toxicity thresholds to reduce the impact on helpful bacteria, animals, and the food chain (Kahru and Dubourguier 2010). Gold, silver, chitosan, and oxidized metals have been shown to have antiparasitic and inhibitory effects on protoscolices in a number of studies. Mahmoudvand et  al. (2014) employed

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different quantities (50–500 mg/mL) of selenium nanoparticles (in the size range of roughly 80–220 nm) for 10–60 min. According to the findings (Mahmoudvand et al. 2014), biogenic Se-NPs at all concentrations have strong scolicidal effects, particularly at concentrations of 500 and 250 mg/mL after 10 and 20 min of application, respectively. Ag-NPs had the most powerful scolicidal effects, according to the results of Norouzi (2017), and can therefore be employed in CE surgery. Malekifard (2017) looked at the effectiveness of gold nanoparticles on hydatid cyst scolices and found that all concentrations of gold nanoparticles had substantial scolicidal effects. All protoscoleces were killed within 60 min by gold nanoparticles at a concentration of 1 mg/mL (Malekifard 2017). Previous research (Rahimi et al. 2015) looked into the scolicidal effects of green-produced silver NPs at various concentrations (0.025, 0.05, 0.1, and 0.15 mg/mL) and exposure times (10, 30, 60, and 120 min) against protoscolices of CHD. The results demonstrated that Ag NPs had significant scolicidal effects at all doses. After 120 min of exposure, the doses of 0.1 and 0.15 mg/ mL indicated mortality rates of 83% and 90%, respectively. Ag-NPs produced by biosynthesis had a 40% scolicidal activity at 0.025 mg/mL for 10 min. According to a report, because they are more affordable, safe, and nontoxic than the commonly utilized chemical materials, biogenic Ag-NPs may be taken into consideration as a viable scolicidal agent for CHD surgery. The study by Safarpour et  al. (2021) suggests an easy, reliable, and useful method for echinococcosis diagnosis. This procedure is based on the development of a sandwich complex between chitosan-gold nanoparticle protein A and an anti-Ag B antibody-bound hydatid cyst antigen (Ag B). By observing a change in color that does not change in the absence of an Ag B biosensor, quick colorimetric results can be obtained. Notably, it also describes a field-applicable method based on blood samples for the prompt detection of infected cases without the need for expert staff or sophisticated equipment. Gold nanoprobes have a long history of usage in biosensing, notably when used to detect DNA, which has been well established. The detection of the microorganisms that cause tuberculosis and malaria was accomplished in a beautiful work by multiplex non-cross-linking colorimetric technology (Veigas et al. 2015). Chitosan has reportedly been used in the past to improve the production of gold nanoparticles and cause observable color changes, according to Mohan et al. (2019). It has been suggested that chitosan-capped gold nanoparticles or gold nanoparticles functionalized or stabilized with organic polymers, such as chitosan nanocomposites, are the best delivery systems since they do not have the toxicity like that of other chemical reagents (Abrica-Gonzalez et al. 2019; Saeed et al. 2020). As a matter of fact, chitosan-based biosensors have shown good sensitivity, stability, and selectivity for the detection of a variety of targets, proteins, DNAs, bacteria, glucose, and a number of tiny biomolecules (Jiang and Wu 2019; Shrestha et  al. 2016). Unexpectedly, colorimetric biosensors and gold nanoparticles have demonstrated considerable uses in diagnostics (Chang et  al. 2019; Aldewachi et al. 2017).

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3.3 Schistosomiasis (Bilharzia) The five species of blood flukes (digenetic trematodes), Schistosoma mekongi, Schistosoma japonicum, Schistosoma haematobium, Schistosoma intercalatum, and Schistosoma mansoni are responsible for schistosomiasis, which affects up to 300 million people annually globally (El-Garem 1998). Three of the five species S. japonicum, S. haematobium, and S. mansoni have been implicated for their role in the pathology of the central nervous system (CNS) (Pittella 1997). At least 30 other mammals are similarly susceptible to infection, but humans are the only known hosts. Schistosomiasis is considered a “man-made disease” by some specialists since it gets transmitted when one comes in contact with water as endemicity necessitates the presence of an intermediate mollusk host (aquatic or amphibious snails) (Zheng et al. 2002). In general, endemicity rates are greater in nations with inadequate sanitary infrastructure and access to clean water. Unfortunately, by damming up or irrigating with contaminated diseased water in impoverished nations in an effort to enhance inadequate sanitary conditions and water supplies, endemicity is frequently increased (Babiker et al. 1985). Moreover, travelers who are cautioned to avoid drinking tap water in countries where the schistosome is prevalent frequently ignore less obvious ways to contract it, such as washing clothes, going barefoot, and bathing. The furcocercous cercariae pierce human skin and cause the first infection. The larva migrates into the venous system, preferring venules and venous plexi, after shedding its tail. Schistosomiasis’s clinical signs can appear at various phases of the parasite’s life cycle and vary depending on the species that is infected. The preferred locations in the human body for each of their distinct species are peribladder veins (S. haematobium), superior mesenteric veins (S. japonicum), or mesenteric veins (S. mansoni), (Pollner et al. 1994). Sixty percent of all schistosomal brain infections are caused by S. japonicum eggs, which are smaller than eggs from other schistosomal species. In contrast, S. mansoni eggs, which are larger, typically only cause spinal cord infections (Pittella 1994). According to Scrimgeour and Gajdusek (1985), S. haematobium can infect either the spinal cord or brain. The CNS is not believed to be a place where adult worms travel, nor is it believed that worm eggs develop into worms there. It is hypothesized that Batson’s plexus serves as a route for entry into the central nervous system. Once within, eggs cause a granulomatous reaction as tissues work to enclose the invading parasite. Granulomas have exudative and necrotic characteristics after persistent infection. Vascular walls and nearby tissue can both have severe necrosis (File 1995).

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3.3.1 Biosensor-Based Diagnosis of Schistosomiasis The Schistosoma genus of trematodes worms causes the neglected tropical disease known as schistosomiasis. It is the second-most common parasitic disease globally. S. mansoni, S. japonicum, and S. haematobium are the principal disease-causing species. In Mediterranean Europe, Southeast Asia, sub-Saharan Africa, South America, and the Middle East, 779 million people are at risk of catching HIV, and it has the potential to affect up to 300 million people annually. Non-endemic areas are also susceptible to it. Schistosomiasis in humans is one of the most common parasite illnesses. Particular freshwater snails act as intermediary hosts in the transmission cycle, which involves the contamination of surface water with excrement (de Albuquerque et  al. 2020; Gryseels et  al. 2006; McManus et  al. 2020). Schistosomiasis can be managed by both prevention and treatment. The two most important ways to avoid schistosomiasis are to improve cleanliness and get rid of snail hosts. To assess the success or failure of schistosomiasis control programs and to ascertain whether control efforts have led to elimination, precise and sensitive diagnostic tests are needed. Diagnoses for schistosomiasis are crucial for identifying and treating infections in both prevalent and non-prevalent locations because they inform case detection, morbidity estimations, and control strategies (Ajibola et  al. 2018; Odundo et al. 2018). Schistosomiasis can currently be diagnosed by molecular, immunological, and conventional parasitological techniques (Katz et al. 1972). Utilizing a microscope to identify parasitic eggs in the urine and feces or using an immunological method (antibody or antigen detection) are two common classical parasitological techniques (van Etten et al. 1994; Odundo et al. 2018). According to Caldeira et al. (2012), the Kato-Katz approach is affordable and practical and gives a high level of specificity. The sensitivity of the test depends on the severity of the sickness, the method, and the post-infection host’s perception. According to Odundo et al. (2018), only 65–86% of existing antibody analyses are fully understood. Recently, clinical sciences and food and drug analysis process control have given screen printing electrode biosensors a lot of attention. These sensors are capable of measuring extremely small concentrations of analytes by identifying changes in potential, current, and conductance brought on by an immunological response (Taleat et al. 2014). According to Lin et al. (2008) and Yang et al. (2009), nanotechnology has been utilized to improve and increase the correctness of existing procedures as well as unexpectedly produce new ones. The creation of extremely sensitive, adaptable diagnostic care devices has shown significant promise when using NPs in immunosensing (Dequaire et al. 2000; Baptista et al. 2008; Wan et al. 2013). Table 3.2 lists a variety of nanosensors that have been utilized to improve the detection of schistosomal infections. In order to identify the S. mansoni genome, Santos et  al. (2019) created an impedimetric biosensor. Using cyclic voltammetry and electrochemical impedance spectroscopy, the biosensor was identified. With a limit of detection of 0.6 pg/L, the created genosensor could identify minute amounts of S. mansoni DNA.

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Table 3.2  List of nanosensor/nano-material used in improving the diagnostic ability against schistosomal infections Nanosensor nano-materials Efficacy used GICA GICA identification strips of S. japonicum in mice, rabbits, buffaloes, and goats show high sensitivity (100% in each spp.) and specificity (100%, 100%, 94.23%, and 88.64%, respectively). When compared with ELISA, the GICA strips exhibited similar sensitivity and specificity in the diagnosis of schistosomiasis in mice, rabbits, buffaloes, and goats. Besides, only 5 μL of serum is required for the test, and the detection can be completed within 5 min AuNPs-Mab/ ELISA’s sensitivity and specificity for detecting ELISA circulating schistosomal antigen (CSA) using AuNPs-Mab was 100% and 97.8%. A more significant positive correlation was detected on the use of AuNPs-Mab/ELISA (r = 0.882). Loading AuNPs with Mab (6D/6F) improved the precision of sandwich ELISA for the determination of CSA, allowing active and mild infections to be identified easily The proposed biosystem detected the S. MPTSAuNPs-DNA mansoni genome sequence in urine samples, probe system cerebrospinal fluid system, and serum in varying amounts. It measured concentrations in urine (27–50 pg/L), cerebral fluid (25–60 pg/L), and serum (27–42 pg/L). The limit detection (LOD) of the biosensor was 0.6 pg/μL. The developed labeled free genosensor was able to detect small concentrations of S. mansoni DNA in complex biological fluids AuNP-IgG Immobilized AuNPs combined with bilharzia nanosensor antibodies proved their diagnostic potential. The detection range of bilharzia antigen in stool samples was 1.13 × 10−1 ng/mL to 2.3 × 103 ng/ mL, with a detection limit of 8.3887 × 10−2 ng/ mL, showing the ability of the nano biosensor for detection of bilharzia antigen in stool samples

Schistosomes spp. S. japonicum

References Xu et al. (2017)

S. mansoni

Kame et al. (2016)

S. mansoni

Santos et al. (2019)

S. mansoni

Odundo et al. (2018)

(continued)

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Table 3.2 (continued) Nanosensor nano-materials used MBA-Fe3O4NPsAuNPsDNA probe system

AuNP-IgG conjugate

NCE-AGs

Efficacy On the changed surface of the electrode, the probe system exhibits an efficient electrochemical response. At varied DNA quantities in the genome, the proposed biosystem was capable of identifying S. mansoni unique nucleotide sequences in cerebrospinal fluid (CFS) and blood samples. At higher DNA concentrations, bio-recognition caused an increase in electron transfer resistance and a decrease in current peaks during electrochemical testing. The established platform had detection limits of 0.781 and 0.685 pg/L DNA for serum and CFS, respectively Conjugate was tested as the analyte with a differing concentration of conjugate soluble egg antigen (SEA). The single response was directly proportional to the SEA concentration. A SEA concentration plot against the current change was obtained. The detection limit of 3.31 × 10−5 ng/mL was obtained with formula 3σ/slope, where σ is the standard deviation of three blank solutions The proposed NCE electrode’s quantitative response and great sensitivity to Abs of S. mansoni are as low as 38 pg, indicating that it may be developed as a site-user, low-cost, and rapid electrochemical immuno-sensor

Schistosomes spp. S. mansoni

References Santos et al. (2017)

S. mansoni

Naumih et al. (2016)

S. mansoni

Shohayeb et al. (2016)

Table 3.3 provides an overview of a number of biosensors developed for the detection of schistosomiasis. Schistosomiasis is the second most common parasite disease in the world, yet little is being done to create biosensors for early detection of the condition. There aren’t many articles on this topic that have been published, and the ones that have are often lacking in figures of worth and terms of optimization. The only study that described a genosensor for S. haematobium detection using RNA isolated from adult worms as the analyte was by Mach et al. (2015). However, various study teams have sought to demonstrate the viability of such a development because the systems testing shows no differences from those seen for other disorders that are obviously present. When contrasted, the detection systems were even more adaptable, allowing for the development of novel and improved devices. These techniques included AP, DPV, ASV, QCM, and EIS, as well as specialized electrochemical markers like silver, tetramethylbenzidine, ferrocene, and ferro/ ferricyanide.

MPPCPE

NCE

GQC

SPCE-16

SPCE

NCE

Au

Au

Au

SPGE

Immunosensor

Immunosensor

Immunosensor

Immunosensor

Immunosensor

Immunosensor

Genosensor

Genosensor

Genosensor

Immunosensor

Mouse Schistosome SEA

Schistosoma DNA and genomic material RNA extracted from S. haematobium eggs S. mansoni DNA

Anti S. mansoni

Inhibitor of S. japonicum

Anti- S. japonicum SEA

SjCAg

Rabbit anti-Schistosome labelled with colloidal gold Anti-S. mansoni

Analyte Rabbit anti- S. japonicum SEA

EIS CV DPV CV

AP

EIS

DPV

DPV

CV

QCM

DPV

ASV

Technique QCM

AuNP-rabbit anti-schistosome

AuNPs/MPTS/oligonucleotide probe

MBA/EDC/NHS/Fe3O4NPs/AuNPs/ thiolated oligonucleotide probe Thiol/capture probe

GA/CS/schistosomiasis antigen

GA/SEA

EDC/NHS/SEA/SjE16

ImRS/NRS or SPA/InRS

GA/CS/schistosomiasis antigen

Fe3O4/Au/MCH/EDC/NHS/SEA

Modification MPA/ME/SjAg

Human specimens Stool sample

Synthetic antibodies Human specimens Human urine

Human serum

Rabbit antibodies Synthetic antibodies Rabbit and human serum Human serum

Sample Rabbit serum

Shohayeb et al. (2016) Wen et al. (2011) Deng et al. (2013) Zeng et al. (2012) Shohayeb et al. (2016) Santos et al. (2017) Mach et al. (2015) Santos et al. (2019) Odundo et al. (2018)

Reference Wang et al. (2012) Xu et al. (2010)

MPA mercaptopropionic acid, MCH 6-mercapto-1-hexanol, ME mercaptoethanol, SjAg Schistosoma japonicum antigen, NHS N-hydroxysuccinimide, EDC 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide, SPA Staphylococcal protein A, SEA native soluble egg antigen, ImRS immunized rabbit’s sera, InRS infected rabbit’s sera, GA glutaraldehyde, MBA mercaptobenzoic acid, SjE16 Schistosoma japonicum calcium-binding protein, Fe3O4 AuNP-IgG gold nanoparticle-antibilharzia conjugate, NP magnetite nanoparticles, SjCAg Schistosoma japonicum circulating antigens, MPTS mercaptopropyltrimethoxysilane, AuNPs gold nanoparticles, MPPCPE magnetic porous pseudo-carbon paste electrode, GQC gold quartz crystal, SPCE-16 16-channel screen-printed carbon electrode array, NCE nanocarbon-screen-printed electrode, SPCE screen-printed carbon electrode, Au gold, SPGE screen-printed gold electrode, QCM quartz crystal microbalance, ASV anodic stripping voltammetry, EIS electrochemical impedance spectroscopy, DPV differential pulse voltammetric, CV cyclic voltammetry, AP amperometry

Electrode GQC

Sensor Immunosensor

Table 3.3  Electrochemical biosensors for Schistosomiasis disease diagnosis

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3.4 The Role of Biosensors in the Early Detection of Cerebral Malaria Malaria, spread by the female Anopheles mosquitoes, is still a significant parasite disease that affects humans globally. The disease is mostly prevalent in tropical and subtropical regions around the world (Jain et al. 2014; WHO 2018). The endemic countries, which are primarily malaria, spread by the female Anopheles mosquitoes, is still a significant parasite disease that affects humans globally. The disease is mostly prevalent in tropical and subtropical regions around the world (Jain et al. 2012; WHO 2018). The endemic countries, which are primarily developing nations, bear a heavy economic cost from the disease. A parasitic alveolate protozoan belonging to the genus Plasmodium is the causative agent of malaria. There are six species in this genus, which are known to infect humans: Plasmodium vivax, Plasmodium cynomolgi, Plasmodium malariae, Plasmodium falciparum, Plasmodium ovale (Plasmodium ovale curtisi and Plasmodium ovale wallikeri), and Plasmodium knowlesi. Considering the World Health Organization’s (WHO) target of eradicating malaria by 2030, the goal can only be reached if every case is correctly diagnosed and handled (Feachem et al. 2019). Routine testing in suspected cases is still unavailable to some of the endemic communities. For instance, in public health institutions in 2018, only 74% of individuals who had malaria suspicions had access to testing procedures (WHO 2018). During this time, there were 228 million cases worldwide, with 405,000 fatalities (WHO 2018). Various control measures have been successful, but they have been constrained by inadequate early diagnostic techniques for identification, particularly in low parasitemia conditions. The identification of asymptomatic people has a significant impact on the malarial dynamics including its spread, control, and perhaps treatment. Diagnostic procedures may aid medical professionals in pursuing additional research into other febrile illness etiologies, preventing severe illness and likely death, and minimizing the presumed usage of antimalarial medications and their related side effects (White 1991). Numerous technologies have up to now tried to get around the difficulties in diagnosing malaria by focusing on rapid diagnostic requirements and early-stage detection of cerebral malaria. Therefore, the chapter thoroughly reviews the most current developments in biosensor technology in this area, with an emphasis on analytical performances, development, and applicability for rapid diagnosis of the most targeted biomarkers of malaria.

3.4.1 Role of Cerebral Malaria-Related Complications in Neurodegenerative Diseases Cerebral malaria is a severe and potentially life-threatening complication of malaria caused by the parasite Plasmodium falciparum (Fig. 3.2). It occurs when infected red blood cells adhere to the blood vessel walls in the brain, leading to inflammation, impaired blood flow, and the accumulation of infected cells, causing cerebral

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Fig. 3.2  Life cycle of Plasmodium spp. (Adapted from Krampa et al. 2020)

edema and increased intracranial pressure. In some cases, this can result in seizures, coma, and death if not promptly treated. While the immediate consequences of cerebral malaria are primarily related to acute brain injury, there may be long-term neurological consequences, potentially linking it to neurodegenerative diseases. Persistent immune responses triggered by the parasite or residual parasites in the brain could create a pro-inflammatory environment that leads to neuronal dysfunction and degeneration, similar to what is observed in certain neurodegenerative disorders. Chronic inflammation and neuronal damage associated with cerebral malaria may contribute to the development or exacerbation of neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). However, further investigation is needed to establish a direct causative relationship between cerebral malaria and these neurodegenerative diseases, as various factors can influence their development and progression. Understanding the potential long-term neurological implications of cerebral malaria could aid in developing targeted therapies to mitigate its impact on brain health.

3.4.2 Biosensors-Based Detection of Malarial Biomarkers With numerous analytical advantages and cost-effectiveness, biosensors and immunosensors have emerged as promising sensing instruments in recent years (Perkins and Bell 2008; Turner 2013). This development has been influenced by the rising demand for point-of-care diagnostic devices. Electrochemical biosensors are one of the sensor types that have drawn a lot of attention in diagnostics due to pivotal design benefits, ease of handling and better performance over traditional laboratory methods (Belluzo et al. 2008; Wang 2008). As attempts are made to improve and

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miniaturize sensor systems to make them easily operable, these properties make them suitable for point-of-care use. Table 3.4 summarizes different biosensor-based detection methods for malarial parasites. Table 3.4  Biosensor detection of various malaria biomarkers Analytes Antigens

Biomarker pLDH (PvLDH, PfLDH) pLDH

Receptor molecule pL1 aptamer

Sensing technique Colorimetric

Transducer –

EIS EIS

Gold electrode GCE

EIS

GCE

HRP-2

Chemiresistive (electrical conductance) –

–

PfHRP-2

–

PfHRP-2

Anti-PfHRP-2

EIS

Gold disc electrodes

PfGDH

Potentiometric (FET)

Pf GDH

Amperometric

Gold microelectrodes Gold-SPE

Amperometric

Gold-SPE

pLDH

Spectrophotometric indicator displacement medium Colorimetric

–

PfHRP-2

ssDNA aptamer (NG3) ssDNA aptamer (NG3) Anti-PfHRP 2 mAb pLDH capture antibody NA

–

PfLDH

Colorimetric

–

PfLDH

Amperometric

SPE

PfHRP-2

FRET

–

pLDH

Amperometric magneto Immunosensor

–

PfHRP2

pLDH

PfHRP-2

pL1 aptamer P38 aptamer (90 mer ssDNA) Anti-HRP-2 antibody Anti-HRP-2 antibody

2008s-biotin DNA aptamer 2008s aptamer Mouse anti-PfHRP-2 antibody Fluorescentlylabeled aptamer (36 mer ssDNA) Anti-HRP2 IgM antibody

Reference Jeon et al. (2013) Lee et al. (2014) Jain et al. (2016) Brince et al. (2016) Paul et al. (2017) Gikunoo et al. (2014) Singh et al. (2018) Singh et al. (2019) Hemben et al. (2017) Hemben et al. (2017) Chakma et al. (2016)

Dirkzwager et al. (2016) Fraser et al. (2018) Sharma et al. (2008) Kenry et al. (2016)

De Souza Castilho et al. (2011) (continued)

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Table 3.4 (continued) Analytes Antibodies

Sensing technique SPR

Transducer Gold disc

Nucleic acids

Quartz crystal microbalance Droplet microfluidic platform SERS Nanoplatform

–

Quartz crystal microbalance

Silver electrode

EIS

SPE

Microfluidic separation and MRR

–

Infected red blood cells

–

–

Biomarker Antibodies of Pf Pf msp2 gene Pf topoisomerase I Pf DNA sequences 18s rRNA gene (Pf and Pv) Pf infected RBCs Infected RBCs

Receptor molecule PfHRP2 Biotinylated probe ds DNA substrate

Reference Sikarwar et al. (2014) Potipitak et al. (2011) Hede et al. (2015)

Magnetic bead and nanorattle Immobilized probe

Ngo et al. (2016)

Monoclonal antibody –

Kumar et al. (2016) Kong et al. (2015)

Wangmaung et al. (2014)

EIS electrochemical impedance spectroscopy, FRET fluorescence resonance energy transfer, GCE glassy carbon electrode, SPE screen-printed electrode, SERS surface-enhanced Raman spectroscopy, SPR surface plasmon resonance

3.4.2.1 Detection of Plasmodium falciparum Histidine-Rich Protein 2 (PfHRP-2) Plasmodium falciparum-specific histidine-rich protein 2 (PfHRP-2) is secreted during parasite growth and development and is involved in the detoxification of heme. The antigen’s high levels of expression throughout the parasite life cycle can be credited for its widespread use in electrochemical and optical immunosensors. Although largely present in the blood, trace levels can also be detected in the patient’s saliva, urine, and cerebrospinal fluid, providing a chance for noninvasive testing (Rodriguezdel Valle et al. 1991; Parra et al. 1991). In the case of the detection techniques, electrochemical techniques have been found to perform better than optical methods. Amperometric immunosensors have utilized nanoparticles, particularly gold (AuNP), for signal amplification (Cao et al. 2011; Liu et al. 2013; Ju et al. 2011). Because of their small size and simplicity in immobilizing bioconjugate probes, there is a larger surface concentration of detecting antibodies that are enzyme-tagged, leading to stronger indicators from the reaction between substrate and enzyme. Magnetic nanoparticles (MNPs) have been used to create a malaria immunosensor that is incredibly sensitive. A monoclonal antibody that binds a specific epitope of the target antigen was tagged with horse radish peroxidase in order to provide an electrochemical signal, while anti-HRP-2 was coupled to magnetic nanoparticles as catch components (De Souza Castilho et  al. 2011). The anti-HRP-2 magnetic nanoparticles were trapped on a magnetic graphite-epoxy composite electrode in a sandwich assay configuration and treated with anti-HRP-2-HRP and

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HRP-2-stimulated serum. According to amplitude measurements, the limit of detection was significantly more than what has been reported in earlier studies (Sharma et al. 2008). However, this technique would need magnetic electrode supports to be applied in the field (De Souza Castilho et al. 2011). Even though antibodies are typically used as capture molecules in biosensing platforms for disease indicators, antibody stability is a challenge for immunoassays. Genetic modifications that increase the permanency of antibodies, as well as the usage of artificial substitutes like aptamers, have been some attempts to get around these disadvantages (Ravaoarisoa et al. 2010). The parental monoclonal antibodies (mAb) and the recombinant Fab fragments had similar binding properties. This technology suggests a financially advantageous substitute to large-scale antibody manufacture for diagnostic purposes by offering the choice of individual antibody fragments with better stability, resistance to denaturation even with prolonged exposure, and affinities. Further, some diagnostic procedures examine the close receptor and target recognition by themselves in addition to adding molecular labels and nanoparticles for enhanced diagnosis (Thukral et al. 2023). Since there are no potentially confusing chemical labels, utilizing such label-free formats reduces the complexity of the assay, the amount of time needed for preparation, and the cost of the analysis. Various other techniques have been designed and utilized to detect PfHRP-2  in patients’ blood, such as indicator displacement assay (IDA) and electrochemical impedance spectroscopy (EIS)-based methods, which have various advantages for the use a detection models in point-of-care testing.

3.4.2.2 Detection of Plasmodium Lactate Dehydrogenase (pLDH) Lactate dehydrogenase is produced by Plasmodium during its intraerythrocytic stages. The glycolytic pathway benefits greatly from the catalytic activity of the enzyme. It is generated by parasites within infected red blood cells that are metabolically active. It serves as a telltale sign of a recent infection. As a result, it is more accurate in locating recent and untreated infections. Aptamer-based sensors that target pLDH appear to be on the rise (Jeon et  al. 2013; Lee et al. 2012; Figueroa-Miranda et al. 2018). Aptamers have several advantages over antibodies, including reduced size, thermostability, a longer shelf life without functional degradation, affordability, simplicity of synthesis, and adaptability. Single-stranded DNA aptamers (pL1 aptamers) have been utilized to target recombinant Plasmodium falciparum LDH (PfLDH) and Plasmodium vivax LDH (PvLDH) in buffer and real samples as a potential method for asymptomatic and early diagnosis of malaria. Impedance measurements are used to identify the interaction between pL1 and the target proteins with great sensitivity and specificity. A colorimetric test was used to measure the intrinsic enzymatic activity of LDH utilizing microbeads that were functionalized with aptamers. Due to the beads’ large surface area for analyte binding, the aptamer-tethered enzyme capture (APTEC) assay produced a LoD for recombinant PfLDH of 4.9  ng/mL (Dirkzwager et  al. 2016; Fraser et al. 2018).

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The aptamer-tethered enzyme capture assay was then integrated into a transportable microfluidic biosensor. The platform addressed some of the assay’s original issues with large sample and reagent volumes while identifying P. falciparum in clinical samples and culture samples with excellent specificity and sensitivity (Dirkzwager et al. 2016; Fraser et al. 2018).

3.4.2.3 Detection of Glutamate Dehydrogenase (GDH) In Plasmodium parasites, glutamate dehydrogenases (GDH) are involved in ammonium assimilation and catabolism of glutamate. Significantly soluble amounts of the enzyme are present during parasite’s development, thus a potent target to detect the presence of the parasite in a patient’s body (Li et al. 2005). By grafting a gold electrode with a thiolated ssDNA aptamer (NG3) particular to P. falciparum (PfGDH), a label-free capacitive aptasensor was created. The sensor has a range of 100 fM–100 nM and produced a limit of detection in serum of 0.77 pM. To create a sensitive and trustworthy miniaturized aptaFET biosensor, the NG3 aptamers were immobilized on interdigitated gold microelectrodes (IDE) and coupled to the field effect transistor (FET). FET-type devices offer the benefit of permitting straightforward and sensitive electrochemical measurements without the requirement of a traditional redox marker. In the presence of similar plasmodial and human proteins, the FET-based potentiometric sensor was highly selective, making it suitable for real-world sample analysis for the detection of malaria (Park et al. 2012; Singh et al. 2018, 2019). 3.4.2.4 Detection of Hemozoin The malaria parasites consume between 60% and 80% of erythrocytic hemoglobin at this stage of their life cycles, resulting in the production of heme and polymerization into insoluble hemozoin crystals (Chugh et al. 2013). Since hemozoin is only found in the digestive vacuoles of parasites, its presence in the blood is a reliable indicator of Plasmodium parasites that are actively engaged in metabolism. It has been demonstrated that surface-enhanced Raman spectroscopy (SERS) has the ability to multiply the hemozoin’s Raman signal by several orders of magnitude (Pagola et  al. 2000). Uninfected lysates do not exhibit a Raman shift when exposed to a gold-coated butterfly wing as a SERS substrate, but parasitized RBCs do. When parasitemia levels were between 0.0005% and 0.005% in the early ring stage, the spectrum markers of hemozoin from infected RBC could be detected. A different SERS method that used synthesized silver nanoparticles inside parasites to achieve close contact with hemozoin demonstrated an ultrasensitive hemozoin detection at 0.00005% parasitemia level in the ring stage (2.5 parasites/L), whereas enhancements of Raman signals occur when hemozoin crystals are in direct contact with metal surfaces (Chen et al. 2016). Although Raman spectrometers are expensive, especially those with high spectral resolutions, several SERS techniques have demonstrated promising results. Magnetic resonance relaxometry (MRR) has been utilized to achieve label-free detection using the paramagnetic characteristics of hemozoin crystals. The MRR technology has achieved early parasitemia detection at a level of 0.0005% when used in conjunction with a microfluidic setup (Krampa et al. 2020).

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There aren’t many known malaria biomarkers; hence, the collection of parasitized RBCs has been suggested as a workaround. In order to find a diverse range of aptamers that specifically bind various epitopes found on parasitized RBC surfaces, a unique microfluidic SELEX (I-SELEX) was used. Monoclonal antibodies were used as capture elements for cells infected with malaria after being immobilized on an AuNP-modified screen-printed electrode. The interaction of monoclonal antibodies with parasitized RBCs resulted in impedimetric changes that allowed infected RBCs to be distinguished from healthy, uninfected RBCs (Garcia 2007; Birch et  al. 2015). In addition to the protein and antibody-dependent detection methods in malaria, various nucleic acid markers have also been explored as an alternative. Additionally, parallel testing may be the best method for delivering healthcare because of its higher throughput, decreased reagent/assay setup, and reduced labor requirements. A multitargeted diagnostic approach between different parasitic species is the main goal of multiplexed malaria testing. To differentiate between passive/resolved or active infections and to discriminate between falciparum and non-falciparum malaria, the most widely used techniques combine PfHRP-2/LDH or PfHRP-2/aldolase (Jepsen et  al. 2012; Iqbal et  al. 2004; Lafleur et  al. 2012; Deraney et al. 2016).

3.5 Applications of Biosensors in the Early Detection of Human African Trypanosomiasis (HAT) Human African trypanosomiasis (HAT), also referred to as sleeping sickness, is a disease that only affects sub-Saharan Africa. The parasite was discovered for the first time in humans in 1902. A trypanosome parasite-group protozoan is responsible for HAT. Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense are the two distinct subspecies. Around 90% of cases are caused by the Trypanosoma brucei gambiense, which causes a persistent infection in patients asymptomatically and increases the likelihood that the disease will progress to an advanced state. When a person is sick, their central nervous system is impacted, which makes it more difficult to treat or control the illness (Büscher et  al. 2017; Bottieau and Clerinx 2019). On the other hand, Trypanosoma brucei rhodesiense infections manifest symptoms weeks or months after first coming into touch with the parasite. This species quickly damages the neurological system by causing an acute infection. The patient’s medical history and course of treatment influence the symptoms in both species (Bottieau and Clerinx 2019). Intermittent fever, pruritus, headaches, lymphadenopathy, anemia, and hepatosplenomegaly are a few typical traces. The meningoencephalitis stage, which manifests as neuropsychiatric and sleep disorders, aberrant movement, limb paralysis, hemiparesis, violent behavior, or psychotic behaviors, is said to start when the parasite penetrates the blood-brain barrier (BBB) (Bonnet et  al. 2015; Masocha and Kristensson 2019; Radwanska 2010).

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One of the neglected tropical illnesses is human African trypanosomiasis (HAT), and early detection is just as crucial to therapy as it is to prevention. The biosensorbased detection assays have also been attempted for its point-of-care diagnosis. The development of the HAT identification system from human blood samples was reported by Tweed-kent et al. in 2012 (Tweed-kent et al. 2012). The assay’s methodology was based on a glassy carbon cylindrical rod electrode (GCCRE) that has been enhanced with carboxylated single-walled carbon nanotubes (CSWCNT), and the assay’s approach was based on an immobilized aptamer created by a Trypanosoma brucei RNA. It is crucial to emphasize the 4.0 fmol/L limit of detection that was attained in actual samples. The hybrid aptasensor that the authors describe is a quicker and more affordable alternative to current commercial tests for diagnosing HAT. It represents a development in the usage of modified ion-selective electrodes (Cordeiro et al. 2021). The diagnosis of HAT is quite challenging due to differences in reactivity toward different parasite species, the symptoms, and affordability of the conventional tests. The current tests include the following: 1. Antibody detection using Card-Agglutination Trypanosomiasis Test (CATT) (Penchenier et al. 2003). 2. Parasite Detection by Lymph Node Examination (WHO 2013), Mini Anion Exchange Centrifugation Technique (mAECT) (Lutumba et al. 2006; Buscher et al. 2009), and Capillary Tube Centrifugation (CTC) (WHO 2013). 3. Stage diagnosis, which involves the use of microscopic techniques to detect trypanosomes in cerebrospinal fluid (Brun et al. 2010; Sekhar et al. 2014). Existing diagnostic techniques require specialized mobile teams that are skilled in doing quick testing utilizing invasive methods, making them difficult and time-­ consuming to apply. The goal is to provide straightforward tests that make it possible to incorporate HAT diagnosis-related activities into the public health infrastructure. Some of the novel HAT staging biomarkers are under investigation and are discussed as follows: Antibody levels such as that of intrathecal IgM, particularly in Trypanosoma brucei gambiense patients, are preferable over WBC counting as a measure for HAT staging (Courtioux et al. 2006). Another area of research being looked into is the modification of immune effectors, such as cytokines and chemokines, for the development of new diagnostic techniques for HAT staging. Early macrophage and astrocyte activation, a rise in inflammatory cytokines, and the appearance of Mott cells (plasma cells expressing IgM) are some characteristics of late-stage HAT neuroinflammation. Two significant sources of inflammatory cytokines and chemokines in the brain are activated astrocytes and macrophages. Both Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense levels of these cytokines and chemokines have been tested to investigate their diagnostic potential (Cordeiro et al. 2021). The measurement of the differences in protein expression between infected and noninfected settings is a different strategy that is currently being researched. Only a few studies have defined the CSF protein patterns for the first and second stages of

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HAT illness. For stage 2 patients, there is a significant increase in immunoglobulin levels (Courtioux et al. 2006; Tiberti et al. 2013), but there are also 73 proteins that differ in expression between the two stages. Osteopontin and beta-2-microglobulin have both been shown to be reliable indicators of patients in the first and second stages (Tiberti et al. 2010). It is now possible to study new protein biomarkers, particularly for differentiating between stages 2 and 1 of the disease, thanks to the development of new tools for protein and peptide analysis (Geiger et al. 2011). Recent research has focused on the alteration of the typical sleep-wake cycle, the most common clinical sign of HAT (Brun et al. 2010). For these studies, polysomnography has been employed. A polysomnography can be used to investigate sleep disorders and includes tests such as an electroencephalogram, electromyogram, and electrooculogram. Other physiological measurements like heart rate and respiratory rate are also recorded. According to studies, stage 2 patients have a high number of SOREMPs during the course of their sleep, not just at night but also during the day (Buguet et al. 2012). For illness staging, it has been suggested to use PCR to amplify particular parasite DNA sequences found in blood, CSF, urine, or saliva samples. For staging HAT illness, the loop-mediated isothermal amplification (LAMP) technique exhibits great specificity and sensitivity. Additionally, this technique amplifies the target DNA at a constant temperature, allowing for the use of the test in low-tech laboratories or in the field in HAT-endemic areas with little equipment (Cordeiro et al. 2021).

3.5.1 American Trypanosomiasis (Chagas Disease) The majority of the nations in South and Central America are endemic to Trypanosoma cruzi (Moncayo 2003). Reduviid bug bites are the most common way to contract the infection, although they can also spread transplacentally, through eating infected guinea pigs, through blood transfusions, or through organ transplants (Busch et al. 2003). Infection has migrated from rural Latin America to the United States and other countries due to rising urbanization and emigration (Dias et al. 2002). Endemicity is at its highest level wherever Triatoma spp. is present. The reduviid bug usually lives in damp environments; however, it has evolved to live in cities (Leiby et al. 2002). When migrants from rural areas with high endemicity donate infected blood to blood banks, transmission via transfusion happens more frequently in urban settings (Sanchez-Guillen et  al. 2002). However, trypanosome-infected transfusions continue to be widespread in many South American nations (Busch 2003). The prevalence of contaminated blood products has decreased in some locations due to increased blood product screening. Immune-suppressed patients have replaced tourists and immigrants as the group in the United States with the highest risk of contracting an infection (Leiguarda et al. 1990). The vector excretes feces containing T. cruzi stages while consuming a blood meal from a potential host, and these stages are then left behind on mucous

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membranes or skin (Kirk and Schofield 1987). During scratching at the site of an insect bite, skin breaches occur that allow stages to enter the human host. These then reproduce by binary fission. These cells shed into the bloodstream, where they travel to distant regions and grow into adult intracellular organisms. Unlike African trypanosomes, T. cruzi only divides after infecting a new cell or after unintentionally ingesting a host. Infected cells burst, releasing infectious parasites as well as potent inflammatory parasitic chemicals that strongly induce a host response (Hall and Joiner 1993). A trypanosome can be seen in serum or CSF, which is required for a conclusive diagnosis (CDC 2003). Blood can reveal intracellular motile creatures when examined under a microscope. Direct visualization of the parasite is unusual during persistent infection. Both chronic and acute forms of infection can be detected by serum antibody detection tests, which are specific and sensitive (Matsumoto et al. 1993). When deciding on a course of treatment, clinical history plays a more significant role than diagnostic tests in identifying how chronic the illness is. Leishmaniasisrelated cross-reactivity can happen (Umezawa et al. 2001).

3.5.2 Advances in Biosensors for the Detection of Chagas Disease The two types of biosensors that have been studied for Chagas disease diagnosis are electrochemical and optical. Amperometric and impedimetric sensors are involved in electrochemical sensors (Erdmann et al. 2013), but only surface plasmon resonance (SPR) transducers are documented for optical sensors (Luz et al. 2015). Pumpin-Ferreira et al. released a study in 2005 about a biosensor for the detection of Chagas disease. The amperometric immunosensor requires an electrochemical contact; hence, the measurements were performed with a potentiostat-galvanostat. Potentiostats are strong pieces of machinery, but they are too huge and heavy to be used as a portable biosensing system. Because these biosensors offer greater miniaturization and integration possibilities for portable systems, further electronics for readout systems need to be created for them. Salinas et al. also published a study on an amperometric immunosensor in the same year (Salinas et al. 2005) with an analysis time of no more than 23 min. In comparison to the ELISA approach, this group achieved a higher level of sensitivity. For the diagnosis of Chagas disease, Luz et al. (2015) created the first biosensor based on SPR transducers. They collected the parameter relating to the presence of antibodies against T. cruzi shown in human serum in around 20 min. In 2016, the same group of researchers found that their immunoassay distinguished Chagas disease from other infectious diseases with a higher percentage of accuracy compared to ELISA and also displayed a higher sensitivity of 100% compared to other diagnostic methods, such as PCR, which has a sensitivity of 90% and an acceptable specificity of 97.2% (Luz et al. 2016). However, because the integration of a light source is necessary for the laser generation and light detectors, the SPR transducing principle now results in high volume and hefty commercial apparatus. The only

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applications for this technology at the moment are lab tests. Additionally, SPR equipment costs more than $50,000 USD, even though optical biosensors can be quite sensitive. This makes it difficult for many researchers to afford such systems (Coltro et al. 2014). In order to diagnose viral diseases using magnetic microbeads, Corina et al. created a portable electrochemical biosensor platform. A mini-portable potentiostat with eight channels that the group created and produced was used to make this platform portable. With assay reading durations of 20 s, they were able to successfully show the platform’s application for the diagnosis of Chagas disease, and the findings they got in terms of sensitivity and selectivity were comparable to those of ELISA. But the system isn’t currently offered in stores. In order to conduct the tests, the technique also necessitates the detection of electrochemical processes, which results in indirect steps. These procedures might be avoided in the future by using different detecting methods, including sound sensors. Additionally, Regiart et al. (2016) reported the development of an electrochemical immunosensor detecting anti-IgM Trypanosoma cruzi antibodies. By boosting the sensor’s active surface area, they used gold nanoparticles to raise its limit of detection. In this study, a detection limit of 3.03 ng/mL was attained. In the same year, Janissen et al. used a nanowire biosensor based on field-effect transistor (FET) technology for the CD protein marker IBMP8-1, achieving a limit of detection of about 6 fM (Janissen et al. 2017). This study illustrates the potential of this highly sensitive biosensor for the management of this condition. Table 3.5 summarizes various nanomaterials that have been used for drug delivery in preclinical studies of Chagas disease.

Hydration

Emulsification

High-pressure homogenization and microemulsion

Mesoporous–silica nanoparticles

Nanoemulsions

Solid lipid nanoparticles

Clove oil Ursolic acid S-Benzyldithiocarbazate

BNZ

CdTe ETZ

Active agent Bis-triazole D0870 Ursolic acid LYC Nifurtimox LYC RAV Nitric oxide BNZ

H2bdtc-SLNs

Poly-εcaprolactone NC-PCL-PLAPEG PACA PCL-PLA-PEG SEDDSs RSNO Multiparticulate benzonidazole polymers – pH-sensitive liposomes Mesoporous silica nanoparticle and chitosan coating Sulfonamides

Composition PLA-PEG

35–100 57.3 127.4

3.3

NI 379

172.2 105.3 ≤200 100–250 100–250 270–500 233

Size (nm) 100–200

Vermelho et al. (2018) Vargas De Oliveira et al. (2017) Carneiro et al. (2014)

Hu et al. (2014)

Vieira et al. (2011) Morilla et al. (2005)

Abriata et al. (2017) Branquinho et al. (2014) Gonzalez-Martin et al. (1998) Branquinho et al. (2017) Sposito et al. (2017) Contreras Lancheros et al. (2018) Seremeta et al. (2019)

References Molina et al. (2001)

mv millivolt, SEDDSs self-emulsifying drug delivery systems, BNZ benznidazole, RAV ravuconazole, PACA poly(alkyl cyanoacrylate) nanoparticles, nm nanometer, PN nanoparticles with poly-ε-caprolactone, ZP zeta potential, NC nanocapsules, PEG polyethylene glycol-polylactide, PCL poly-ε-caprolactone

Colloidal chemistry Extrusion

Nanoprecipitation Self-emulsifying Ionotropic gelation Nanoprecipitation and freeze-drying

Nanoprecipitation Nanoprecipitation

Preparation method Simple emulsification

Quantum dots Liposomes

Nanomaterial Polymeric nanoparticles

Table 3.5  List of different nanomaterials with varying composition that have been used for drug delivery in preclinical studies of Chagas disease

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3.6 Advances in Biosensors for the Detection of Toxoplasmosis Toxoplasmosis are caused by the protozoan parasite Toxoplasma gondii (BergerSchoch et al. 2011). Even though many infections only cause minor symptoms like weariness, fever, and enlarged lymph nodes, they can cause serious disease and even death in people with compromised immune systems or when the parasite is passed on genetically (Xiao and Yolken 2015). The identification of certain antibodies against the Toxoplasma parasite is frequently required for the diagnosis of toxoplasmosis. To get around the shortcomings of traditional methods, poor sensitivity, low specificity, and device complexity, a number of tools have been developed, including electrochemical, optical, and piezoelectric devices. According to Nambiar and Yeow (2011), biosensors have a number of benefits over traditional analytical techniques, including excellent selectivity and sensitivity, the potential for miniaturization and portability, quick response, small sample quantities, real-time detection, and low cost. Electrochemical sensors have been utilized to detect specific IgG anti-T. gondii antibodies, which serve as important markers for the determination and confirmation of toxoplasmosis infection (Li et al. 2017). Another detection method involves the use of an electrochemical immunosensor based on T. gondii IgM antibodies (Tg-IgM) to verify the presence of toxoplasma infection (Jiang et  al. 2013). The majority of biosensors described in the literature for toxoplasmosis rely on immunoassays to detect anti-T. gondii antibodies. In one approach, an agglutination-based piezoelectric immunoassay was developed to directly detect anti-T. gondii immunoglobulins in infected rabbit serum and blood. This method utilizes antigen-coated gold nanoparticles that undergo specific agglutination in the presence of the corresponding antibody, leading to a frequency change detected by a piezoelectric device. The system demonstrated sensitivity to anti-T. gondii antibody dilution ratios as low as 1:5500 (Wang et  al. 2004; Ding et al. 2005) developed an electrochemical biosensor employing enzyme-catalyzed amplification. The surface of a gold electrode was immobilized with T. gondii antigen to capture anti-Toxoplasma IgG, followed by the addition of anti-Toxoplasma IgG horseradish peroxidase conjugate. Transduction methods such as quartz crystal microbalance, electrochemical impedance spectroscopy, and cyclic voltammetry were employed, achieving a detection limit of 1:9600 in dilution ratio. Luo et  al. (2013) utilized two aptamers with high affinities to antitoxoplasma IgG in the development of a quantum dots-labeled dual aptasensor. The presence of anti-toxoplasma IgG leads to the formation of an aptamer-protein-aptamer sandwich complex, which is captured on a multi-well microplate. The fluorescence emitted by quantum dots is then measured, allowing for quantitative analysis. The aptasensor demonstrated linearity within the range of 0.5–500 IU, with the lowest detection limit of 0.1 IU. Another detection method, described by He et al. (2015), utilized magnetic fluorescent nanoparticles in the development of a genosensor for the detection of T. gondii DNA oligonucleotides. This fluorimetric method achieved a limit of detection of 8.339 nM.

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Alves et al. (2019), developed an immunosensor for detecting anti-Toxoplasma antibodies, which can distinguish various stages of infection. Although IgM is commonly used as a marker for toxoplasmosis, it is not detectable in some patients, making the measurement of IgG a more reliable diagnostic tool (Medawar-Aguilar et al. 2019). Glyco-sylphosphatidylinositol glycolipid-anchored proteins (GPI-Aps) are important for cell signaling and communication during infectious diseases and are present on the surface of T. gondii, T. brucei, and P. falciparum (Tsai et  al. 2012). GPI-Aps can be used for detecting anti-GPI IgG and IgM antibodies in seropositive patients (Echeverri et  al. 2020). A simple colorimetric method based on gold nanoparticles has been developed using synthetic polymorphic peptides derived from the GRA6 antigen, specific for type II T. gondii, which can efficiently detect anti-GRA6II antibodies in serum samples. This biosensor-based immunoassay using AuNPs conjugated with polymorphic synthetic peptides can be used as a serotyping device (Sousa et al. 2021).

3.7 Application of Biosensor in Early Detection of Neurocysticercosis Taenia solium, commonly known as the pork tapeworm, is a helminth parasite that is responsible for causing a condition called cysticercosis (Fig. 3.3). Cysticercosis occurs when animals and humans become infected with the eggs of T. solium, often through the consumption of contaminated pork. Neurocysticercosis is a parasitic infection of the central nervous system caused by the metacestode of the tapeworm T. solium (Garcia et al. 2003). It is a leading cause of acquired epilepsy worldwide, especially in developing countries. Early detection of neurocysticercosis is critical for effective treatment and prevention of seizures and other neurological complications. The eggs of T. solium hatch and release oncospheres that have the ability to invade the nervous system of humans. This invasion can lead to the development of adult-acquired epilepsy and other neurological complications. Ingesting raw or undercooked meat from pigs infected with cysticercosis can result in the development of a tapeworm infection known as taeniasis in humans. Patients with taeniasis may experience various symptoms including epigastric discomfort, nausea, insomnia, anorexia, irritability, diarrhea, and weight loss. Detecting T. solium infection is crucial for early diagnosis and effective management of the disease. Different immunoassays have been developed to detect T. solium infection in both infected humans and livestock animals. However, these methods often require centralized laboratory facilities and are time-consuming, labor-­ intensive, and have longer turnaround times. This can delay the diagnosis and treatment of infected individuals. To overcome these limitations, there is a need for innovative diagnostic approaches that are rapid and sensitive and can be performed at the point of care. Biosensors offer a promising solution in the early detection of T. solium infection. These analytical devices utilize bioreceptors to recognize and interact with specific molecular targets, producing a detectable signal that indicates the presence of the

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Cysticerci develop in pig muscles

Cysticerci can lodge in human tissues such as brain, eyes, muscles

Contaminated food ingested by humans

T. solium adult worm lodges in human intestine, discharges proglottics full of eggs into the environment via feces

Pigs by coprophagia and humans by contaminated food/water or autoinfection acquire parasite Soil contamination by open defecation

Fig. 3.3  Lifecycle of Taenia solium. (Adapted from Siddiqua and Habeeb 2020)

infection. Biosensors can provide several advantages in the diagnosis of these infections, including rapid results, minimal sample requirements, portability, and potential for on-site testing. By utilizing biosensors, healthcare providers can obtain real-time information about the infection status, enabling timely intervention and appropriate treatment (Zhao et al. 2019; Kulkarni and Goel 2020). Biosensors have emerged as a promising tool for the early detection of this disease. Biosensors are analytical devices that combine a biological recognition element (such as an enzyme or antibody) with a transducer to convert a biological signal into a measurable signal. Biosensors offer several advantages for the early detection of neurocysticercosis, including their high sensitivity, specificity, and selectivity. They can detect the presence of the parasite’s antigens or antibodies in various biological samples, such as serum, cerebrospinal fluid, and saliva. One type of biosensor that has been developed for the early detection of neurocysticercosis is the electrochemical biosensor. This biosensor consists of a working electrode, a reference electrode, and a counter electrode. The biological recognition element is immobilized on the working electrode, and the transducer measures the electrochemical signal generated by the interaction between the recognition element and the target antigen or antibody. The electrochemical biosensor can detect the presence of the parasite’s antigens or antibodies in biological samples with high sensitivity and specificity. Another type of biosensor that has been developed for the early detection of neurocysticercosis is the optical biosensor. This biosensor utilizes light to measure the interaction between the biological recognition element and the target antigen or antibody. The optical biosensor can detect the presence of the parasite’s antigens or antibodies in biological samples with high sensitivity and selectivity.

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Biosensors offer several advantages for the early detection of neurocysticercosis over conventional diagnostic methods, such as ELISA and PCR.  Biosensors are portable, simple, and rapid, and they can provide real-time results. They can also detect low levels of the parasite’s antigens or antibodies in biological samples, which may not be detectable by conventional methods. The detection of neurocysticercosis, caused by the infection of T. solium (pork tapeworm) can be facilitated by various biosensor-based approaches. One such method involves the use of a lateral flow test utilizing nano-sized up-converting phosphor (UCP) reporter particles and a portable analyzer. This test detects antibodies in serum samples that react with bacterial-expressed recombinant T24H, a specific marker for neurocysticercosis cases (Corstjens et al. 2014). The UCP-LF assay incorporates TSOL18 and GP50 antigens, which are known to be highly protective, immunogenic, and specific for the early diagnosis of cysticercosis (Gomez-Puerta et al. 2019). Compared to ELISA, the UCP-LF assay demonstrates higher sensitivity (93.59% for TSOL18 and 97.44% for GP50) and specificity (100% for both antigens), providing a rapid, small-volume and reliable method for cysticercosis diagnosis (Zhang et al. 2021). Another approach involves the use of a localized surface plasmon resonance (LSPR) biosensor utilizing colloidal gold nanoparticles (AuNPs). This biosensor detects T. solium antigens and demonstrates the ability to differentiate between positive and negative human serum samples, representing diseased and non-diseased individuals with neurocysticercosis (Arcas et  al. 2021). The LSPR biosensor, employing AuNPs synthesized through a specific protocol, exhibits improved stability during biofunctionalization and offers potential for the diagnosis of neurocysticercosis (Soares et al. 2018). In addition, a biosensor based on quantum dot aptasensor (Q-DAS) technology has been developed for the detection of antitoxoplasma IgG, which is relevant in Toxoplasma screening. This biosensor employs specific aptamers as coating and detection probes, enhancing sensitivity compared to conventional antibody-based assays (Luo et al. 2014). Peptides have also gained interest in biosensing for their unique characteristics, such as biocompatibility, stability, ease of synthesis, and sequence versatility. Peptide-based biosensors have been explored for the enhanced detection of pathogens, including T. solium. These biosensors offer advantages over antibody-based assays in terms of resistance to harsh conditions and suitability for on-field applications (Karimzadeh et al. 2018). Among various transduction systems used in biosensors, electrochemical and optical platforms are the most prevalent, followed by mass-based systems. Bioreceptors such as antibodies, nucleic acids, aptamers, peptides, and bacteriophages have been employed to construct these biosensors, with the choice of bioreceptor being crucial for achieving reliable detection with high sensitivity and specificity (Bhardwaj et al. 2017; Wu et al. 2014, 2015; Vidic et al. 2019; Vizzini et  al. 2021; Bruno 2014; Islam et  al. 2022; Karimzadeh et  al. 2018; Qiao et al. 2020; Tertis et al. 2021; Karoonuthaisiri et al. 2014; Anany et al. 2018).

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3.8 Conclusion Despite numerous efforts from committed individuals, the number of new cases and fatalities from neuro-parasitic diseases continue to be frightening. Neuroparasitic diseases have a severe influence on the entire world. The challenges are enormous, ranging from accessing isolated and unsafe regions to having treatments available to help entire communities. To expedite the right diagnosis and, consequently, the treatment, low-cost and miniature equipment like biosensors can be used in these conditions. In order to diagnose neuroparasitic disease early on, biosensors have become a viable tool. In comparison to traditional diagnostic techniques, they have a number of advantages and have excellent levels of specificity, selectivity, and sensitivity for detecting the presence of the parasite’s antibodies or antigens in a variety of biological samples. Biosensors have the potential to improve the diagnosis and treatment of neuro-parasitic disease and reduce the burden of this disease worldwide.

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4

Green Nanotechnology for Addressing Neurodegenerative Disorders Bindiya Barsola, Shivani Saklani, and Diksha Pathania

Abstract

This potential investigates the unique and state-of-the-art interaction of green nano systems with neurodegenerative diseases (NDDs) for producing monitoring and device implants, focused drug delivery methods, surgical prosthesis, therapies, administration, nano scaffolds for neurogeneration, and immune development. This chapter highlights the ongoing progress in the use of green nanotechnology in tackling the neurodegenerative disorders. The use of nanotechnology to effectively and securely transfer biological agents through the blood-brain barriers (BBB) along with early detection, neuroprotective strategies, gene therapy, and targeted theranostics might turn out to be a substantial addition to therapeutic neuroscience by bringing safety concerns at the forefront. Keywords

Green nanosystems · Phyto-nanotechnology · Phytochemicals · Nanoparticles · Neurotoxicity

B. Barsola · S. Saklani School of Biological and Environmental Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, India D. Pathania (*) Department of Biotechnology, MMEC, Maharishi Markandeshwar University, Mullana, Ambala, Haryana, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_4

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4.1 Introduction The phrase “neurodegenerative disorders” (NDDs) encompasses a broad spectrum of biological, genetic, and/or episodic conditions that are typified by a persistent loss of neuronal subtypes (Modi et al. 2009). Some of the very infamous examples of neurodegenerative disorders of the current times are Parkinson’s disease, Huntington’s disease, multiple sclerosis, Prion disease, spinocerebellar ataxias, and Alzheimer’s disease. Impaired memory and cognition are hallmarks of AD, whereas in Parkinson’s disease, the central brain’s nigrostriatal dopamine neurons that lead to degeneration led to severe motor deficits such as bradykinesia, stiffness, hypokinesia, and an involuntary tremor (Jankovic 2008; Jiménez-Balado and Eich 2021). Huntington is a genetic defect that causes mutation in the gene leading to protein accumulation in brain (Brandebura et al. 2023). Nanotechnology has the power to change neuroscience-based knowledge and healing practices, and it may be used to make important pledges for the creation of nano-enhanced drugs to aid in the cure of NDDs (Bhattacharya et al. 2022). Target organs and tissues may be stimulated, reacted to, and interacted with by nanotechnological tools in order to generate intended bodily reactions while minimizing adverse side effects. Furthermore, compared to current pharmacological methods like the blood-brain barrier (BBB), nanotechnology may make it possible to alter intricate biological structures with higher timing and specificity (Modi et al. 2009).

4.2 Neurodegenerative Diseases: Theranostics NDDs are characterized by perpetual loss of neurons, glial cells, and neuron networks in brain resulting in ataxia and dementia. Numerous neurotoxic occurrences, especially chronic inflammation, mitochondrial dysfunctions, and the generation of reactive oxygen species (ROS) can lead to neurodegenerative diseases (NDDs). These diseases cover an extensive array of therapeutically and pathologically varied disorders characterized by gradual long-term impairment of memory and diminished abilities in everyday life. Alzheimer’s disease and Parkinson’s disease are the two most debilitating diseases in the today’s world. NDDs currently impact about 50 million individuals globally, with the number expected to rise to 130 million by 2050. NDDs are anticipated to become the second leading cause of fatalities in the 20 years to come, according to the World Health Organization (WHO) (Chen et al. 2022). Among NDDs, 60% of cases are represented by Alzheimer’s sickness, and approximately 24 million individuals are suffering with the problem of dementia. Destruction of dopaminergic neurons leads to Parkinson’s disease, which ends up in severe motor deficits such as stiffness, hypokinesia, resting tremor, and bradykinesia. NDDs and their affected neurons have been given in Fig. 4.1. The pathophysiology and cause of neurodegeneration for each NDD is distinctive, but they all are characterized by neural inflammation, neuronal degenerate ion, misfolded aggregates of protein, oxidative stress, and dysregulated autophagy (Dugger and Dickson 2016; Kabanov and Gendelman 2007; Ferri et  al. 2005; Tiwari et  al. 2019).

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Fig. 4.1  Schematic diagram of Neurodegenerative diseases and affected neurons

Mitochondria serves as an essential part in the oxidative balancing and metabolic functioning of neurons; as a result, mitochondrial dysfunction is linked to NDDs. Thus, mitochondria are currently being studied as a potential therapy target for NDDs (Zhang et al. 2021). Neurodegenerative diseases (ND) are essentially agerelated ailments that are becoming more prevalent globally as the old population has grown in the past few decades. However, the absence of appropriate therapy is the real issue. It is necessary to diagnose NDDs as soon as possible for delaying the progression of neurons degeneration. Biomarker expressions play a vital role in early-stage diagnosis as clinical manifestations are not that much apparent even after decades of NDD occurrence (Bhattacharya et al. 2022). Targeted molecular interactions are rendered by the integration of nanoscience in physiology and cell biology. Nanomaterials have a great degree of the precision in their interactions with biological entities at the fundamental, molecular level, which allows their use in targeted drug deliveries (Silva 2006). Nanotheranostics is one of the most emerging integrative approaches to deal with the increase in the prevalence of NDDs. Theranostics for the management of NDD are primarily symptomatic due to the paucity of early-stage biomarkers and the inability of medications to traverse the blood-brain barrier (Chaudhary 2022). Use of green neuro-nano system has been increasing rapidly in the therapeutics of neural ailments due to the targeted delivery, more specificity, and lesser probability of toxicity and side effects. Biosensors are growing as one of the subsequent-generation instruments for monitoring and identifying physiochemical alterations that correspond to neurological diseases. The signals produced by optical, magnetic, electrochemical, and mechanical biosensors can be improved by nanoparticles. Recent research points to nanomaterial-based biosensors as a potential replacement for the traditional, labor-intensive methods of identifying NDD biomarkers (Gautam 2022).

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4.3 Phyto-Nanotechnology: Through the Blood-Brain Barrier Sustaining the homeostasis of the cerebral microenvironment depends on three barriers profoundly on the blood-brain barrier (BBB) followed by arachnoid barrier and blood-cerebrospinal fluid barrier (BCB) for structural and functional integrity, which is required for the smooth functioning of nervous system (Kadry et al. 2020). Blood-brain barrier (BBB) is a complex web of blood vessels with endothelial cells that inhibit the arrival of undesirable matter in brain. Semipermeable nature of BBB acts as major obstacle for the migration of therapeutical molecules into CNS across BBB (Tiwari et al. 2019). Presence of BBB made the progress of theragnostic more challenging. Green-synthesized nanomaterials (1–100  nm) have the tendency to counteract all the barriers. Due to their nano size, they are lipid soluble, exhibit association at the molecular level with the neural system, efficient to cross BBB, and can sustain for longer duration in the in  vivo conditions (Silva 2006). Furthermore, the physicochemical aspects of nano techniques, such as magnetic, visual, electrical, and mechanical qualities, as well as chemical aspects (surface chemistry, reactance, and absorption), can be tailored to the specific application. Because of their flexible and exceptional physicochemical and topological properties, nanotechnologies have been employed as key transmission vectors for precise drug delivery, neuroimaging modalities, neural protection strategies, neurosurgical procedures, and neurodegeneration scaffolding in NDDs with the capability to travel across the BBB (Chaudhary 2022). Phyto-nanotechnology has been emerged as the most promising technology in the NDD management. Diffusive lipid membrane, passive and active transport, junction transport, carriers, transcytosis, and endocytosis mediated by receptors are the possible ways to traverse the BBB and can be attained only with the advancement in the field of phyto-nanotechnology. P-glycoprotein process also mediates the traverse to BBB (Kadry et  al. 2020; Bhattacharya et  al. 2022). The evaluation of green nanoscience for a variety of applications in NDDs, such as neuro-generation, theranostics, image-mediated evaluation, drug administration, and drug development, is still in its infancy despite their exceptional benefits in neurosciences. Green-synthesized nanoparticles enhance the neuroprotection, neural regeneration, and trans-mitigation of targeted phyto-nanomedicines and have a significant role in neuropathophysiology as they have the potential to minimize the impact of reactive oxygen species (Silva 2006). Applications of green-synthesized nanoparticles in neurosciences are given in Fig. 4.2.

4.4 Management of NDD with Green Neuro-Nano Systems The fundamental cause of the toxicology of conventional nano-systems is the antecedents and fabrication processes employed. Nanocarriers must be used in order to evaluate the maximum impact on CNS cells. Contrarily, green approaches to synthesize nanoparticles require fewer toxic chemicals with lesser energy for their

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Fig. 4.2  Representation of Applications of green-synthesized nanomaterials in neurosciences

formulations. Hazardous chemicals are replaced by greener sources such as botanical extracts (flowers, leaves, stem, bark, fruits, seed, and roots) their phytoconstituents (alkaloids, flavonoids, saponin, tannins, terpenoids, phenolic acids), and microbes (yeast, fungi, algae, bacteria, viruses) (Chaudhary 2022; Pathania et al. 2021). Essential oils are being leveraged to produce nanoparticles for the treatment of many diseases, and their loading in neuro systems has shown improved effectiveness in combating illness (Pathania et al. 2021). During the formulation of nanoparticles with greener chemistry approaches, the physicochemical properties can be optimized substantially by the regulation of phytochemical processes and parameters including the concentration used, type, medium of reaction, duration, and temperature. Green neuro-nano system interface has become a promising technique for the diagnosis, surveillance, and the therapeutic management of NDDs. Reduced particle size, large surface area of specificity, configurable physicochemical characteristics, and extensive surface functions are the main attributes, which make the green nanotechnology more efficient in the management of NDDs. The key characteristic of green nanomaterials for the management of NDDs is their biological compatibility in regard to neurological toxicity, histocompatibility, toxicity to cells, genome damage and toxicity, and tumor growth, which suggest their enormous potential for preventing NDDs. Green nano systems have been developed in recent years for fighting NDDs, such as implantable and diagnostic tools that include catheters, biological sensors and stunts, and pharmaceutical delivery tools like nanoliposomes with the capability of traversing the blood-brain barrier and function as antibodies, establishing immunity, controlling and treating both initial and subsequent symptoms, biological compatibility in operating prostheses, and particular therapies and immunization (Chaudhary 2022). Figure 4.3 depicts the green neuronano system interface in management of NDDs.

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Fig. 4.3  Diagram of Green neuro-nano system interface in management of NDDs (Chaudhary 2022)

4.5 Significance of Phyto-Nanomedicines in the Treatment of Neurodegenerative Disorders The advancement of science and technology has produced several advancements that have improved all facets of human life (Saklani et al. 2023). Green neuro-nanosystem has an emerging therapeutic potential in the field of biomedical sciences. Advances in the integrative medicine and contemporary sciences have potential in the treatment of ND. To minimize the side effects of synthetic drugs used for the treatment of NDDs, it has become necessary to move toward the best alternatives of these synthetic drugs. The sole symptomatic alleviation offered by the earlier treatments for NDDs is an increase in lifespan of few years. Targeted drug delivery and their precise administration are vital elements in the development of phyto-­ nanomedicine. Consequently, using medication delivery systems based on nanotechnology can boost a treatment’s efficacy. Many medicinal plants are known to scavenge reactive oxygen species and have antioxidant as well as anti-inflammatory potential, which elicits their use in neural science incorporation with nanotechnology (Silveira et  al. 2021). Therapeutic phyto-conjugates with nanoparticles are recently trending in the production of neuro-phyto-therapeutics and emerging as most promising technique to deal with the neurological ailments (Thukral et  al. 2022). Phytochemicals are known to exhibit properties like antioxidative, antiinflammatory, anticancerous, antibacterial, anti-amyloid, and antiviral capabilities, which make them as potentially effective therapeutic agent, and they are also utilized because they exhibit chelation and have capability of providing stability to

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Fig. 4.4  Schematic illustration of Role of phyto-nanomedicines in the treatment of NDDs

nanoparticles (Barsola et al. 2023). Due to specificity of target and minimal side effects, the use of phyto-nanomedicines has become more prevalent. Plants belonging to different families such as Acorus calamus (Acoraceae), Allium sativum (Amaryllidaceae), Centella asiatica (Apiaceae), Curcuma longa (Zingiberaceae), and Celastrus paniculatus (Celastraceae) have been used in the treatment of NDDs. Phytochemicals of the plants are well known for the treatment as they can induce apoptosis of neurons by the beta-amyloid suppression and downregulation of Bcl-2, and SAC (S-allyl cysteine) prevents oxidative damage; reduces lipid peroxidation; enhances the activity of oxidative markers such as SOD, CAT, and GPx; suppresses neurotoxicity by scavenging free radicals and upregulation of GSH levels; inhibits the formation of fibril and activity of peroxidases and accumulation of amyloid; enhances neurotrophic activity; and maintains balance of oxidative markers. Phytochemicals such as alkaloids attenuate the NDD development by raising the level of GABA and inhibiting the activity of enzyme acetyl-cholinesterase (Bhattacharya et al. 2022). Phyto-mediated nanodrugs produced by incorporating green synthesis with nanosystem-based drug delivery can enhance the transmigration of biomolecules across BBB and also reduce side effects by maximizing the pharmacodynamics of phyto-mediated nanodrugs (Tiwari et al. 2019). Terminalia arjuna, Gloriosa superba, Aquilegia pubiflora, and Aspergillus austroafricanus have been explored for the synthesis of gold, silver, and ZnO nanoparticles, which aid in the treatment of neurodegenerative diseases (Thukral et  al. 2022). Role of phyto-nanomedicines in the treatment of NDDs has been given in Fig. 4.4.

4.6 Decisive Outlook of Phyto-Nanotechnology for Addressing NDD Due to the complexity of neuropathophysiology, clinical trials and more research are required to get efficient therapeutic biomarkers for NDDs. Incorporation of modern-age technology with green nanosystem has become an efficient and more reliable way for the management of NDDs. Implementation of green nanosystems

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made from botanical extracts, microbes, biome-mediated precursors, reclaimed waste products, exosomes, and protein-mediated bio-nanomaterials in the biomedical sciences is flourishing day by day as these green nano system approaches are inexpensive, environmentally friendly, biologically compatible, nontoxic, multifunctional, and inexhaustible (Chaudhary 2022). Efficacy of green neuro-­ nanosystem is more due to adequate surface area of neuro-nanosystems, which also enhances the probability of association with biomarkers, drug delivery molecules, and with degenerating cells. Nanomaterials boost scanning techniques, image quality, and signal magnitude, making it easier to distinguish the brains of NDDs from those of other people. Many biosensors, meantime, exhibit great sensitivity on the identification of NDDs biomarkers in biological fluids when paired with various nanomaterials (Chen et al. 2022; Sonu and Chaudhary 2022). The green nanosystems have the ability to sustain neurological health in the midst of neurogeneration and regulate the production of neural secretions by addressing the problems of neurotoxicity. There is still paucity of the information regarding the implementation of greener nanosystems in the management of various NDDs due to the problems related with the efficiency, formulations, stability, scalability, specificity, and their standardization, which further includes complications of total yield, purification, and disparities in phytoconstituents due to the altitudinal variations. In spite of these, inadequate encapsulation utility, bioaccumulation, irregular and uncontrolled cellular processes, biological fluctuations, and hostile conditions are some other attributes responsible for limiting the implementation of green-neuro-nanosystem for its commercial utilization. There is a need to address the cellular association, mechanism, interaction, and pathogenecity of bio-mediated nanomaterials in humans for the theranostics of NDDs. More animal trials, advancement in theranostics, innovative solutions, in  vitro and in  vivo assessments, and clinical trials of phyto-mediated nanosystems for the management of NDDs are required to cover the gap between animal modelling and conceptual evaluations.

4.7 Conclusion Nanoengineered drugs can be a breakthrough in neuromedicine as the blood-brain barrier restricts the conventional medication delivery techniques, which are unable to adequately restore cyto-architecture and connexion patterns that are crucial for normal functioning in NDs. The simultaneous developments in neuroscience and nanotechnological research will have a considerable positive impact on nanotechnology research targeted at CNS regeneration and neuroprotection. With the potential to transform neurodegenerative disease detection and therapy, nanotechnology could give patients fresh hope and deepen our knowledge of these intricate disorders. It’s crucial to remember that a lot of these possibilities are still in the research and development phase, and regulatory clearance and additional research may be needed before they can be used in clinical settings.

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5

Nanotherapeutics for Neurological Disorders Bilachi S. Ravindranath and Ananya Grewall

Abstract

The World Health Organization (WHO) report on “Neurological disorders: Public health challenges” (2006), a collaborative international survey involved 109 countries. Its projection reveals one billion population to be affected globally by 2030. The advent of nanotherapeutics has significantly leveraged the field of therapeutics with the development of nanosized materials in biomedical diagnosis and therapy of neurological diseases/disorders (ND) specifically. The inclusion of functional nanomaterials includes polymeric nanomaterials (micelle, nano-capsule, and dendrimer) and lipid-based nanoparticles (solid lipid nanoparticle and liposomes) as deliverables at the cellular and molecular levels. It has led to concerted progress in recent approaches to molecular diagnosis, gene/drug delivery, and combinatorial therapy. In this chapter, we will orient the progress and advancements in the novel approaches of nanomaterials as nanotherapeutics in the diagnosis, management, inhibition, and prospects of varied nanomaterials in the diverse application of nanomedicines in ND. Keywords

Neurological disorders · Nanomaterials · Nanomedicine · Nanotechnology · Nanotherapeutics

B. S. Ravindranath (*) Manipal Institute of Technology, Manipal, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India e-mail: [email protected] A. Grewall Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_5

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5.1 Nanotechnology in Theranostics of Neurological Diseases/Disorders Nanotechnology is an evolving field comprising nanoparticles, nanopolymers, and nanodevices to diagnose and treat various diseases, including neurological disorders (ND). NDs are a broad category of morbidities in the central nervous system (CNS) and peripheral nervous system (PNS). Neurological disorders like stroke, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), multiple sclerosis, Parkinson’s disease (PD), cerebral aneurysms, ataxia, seizures and epilepsy, brain tumors, and traumatic stress disorders affect multiple organs, such as the brain, cranial and peripheral nerves, autonomic nervous system, spinal cord, nerve roots, and the neuromuscular junction. These disorders have a considerable impact on the patient’s quality of life and require proper diagnosis and treatment (Sun et al. 2019). World Health Organization’s (WHO) Global Burden of Disease (GBD) report focuses on the drawbacks of conventional epidemiological and health-based statistical analysis and has neglected the seriousness of the burden of neurological diseases/disorders by only focusing on mortality rates rather than considering disability rates. It highlights the disproportionate analysis of the serious burden of ND in lower-income and developing nations (Sun et al. 2019; Feigin et al. 2020). WHO, in collaboration with multiple governmental and nongovernmental organizations globally, is making efforts to address the challenges posed by the ND globally. Based upon its analysis, it has prioritized and ranked below ND as the top disease/disorder of major public health concern: (1) stroke, (2) epilepsy, (3) AD, (4) PD, (5) multiple sclerosis (MS), (6) migraine, and (7) traumatic brain injury (WHO 2006). Nanomaterials are various kinds of particles in the nanoscale range. These materials are available in varied classes containing minute mass of matter in the range of 1–100 nm. Nanoparticles (NPs) are made of different dimensions, including zero-­ dimensional (0D), one-dimensional (1D), two-dimensional (2D), three-dimensional (3D), etc. (Tiwari et al. 2012) (Fig. 5.1). These wide choices of NPs are significant in detecting, orienting, diagnosing, and therapy in biomedical science. NPs, in combination with drug compounds, are effective in achieving the targeted delivery to the specific intended targets in the human body (Chaudhary et al. 2023). NPS with different structures is modified to suit the diagnostics and therapeutics capabilities of neurological diseases. This chapter specifically focuses on the diverse class of NPs employed in the field of nanotherapeutics.

5.2 Advancements of Nanotechnology in Theranostics Nanotechnology has exhibited great promise in medical diagnostics and therapy due to its ability to manipulate materials at the nanoscale level (Gautam et al. 2022). Listed below are some recent advancements in the biomedical field: Nature-based nanoparticles (NPs) can be engineered to deliver drugs to specific sites in the body, improve drug efficacy with high speed, and reduce side effects by being eco-friendly and with biocompatibility being nontoxic and cost-effective

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Fig. 5.1  Depiction of nanoparticles in multiple dimensions with varied applications

(Panda et al. 2020). NPs include the newly synthesized varieties of nanocarriers like carbon nanotubes, metal-based NPs, polymer conjugates, micelles, and liposomes to develop blended nanomedicine (Sharma et al. 2019). Magnetic nanoparticles (MNPs) possessing magnetic properties are being considered with higher magnetic moments to enhance the functionalities in the applications of biomedical needs for the identification, diagnostics, and therapy of neurological conditions. Gold nanoparticles (AuNPs) are undoubtedly involved as significant nanomaterials for a varied range of applications in biomedical science (Berners-Price and Filipovska 2011; Richards et al. 2002). Quantum-sized AuNPs (AuNPsQ) were hybridized with porous CaCO3 to formulate a fluorescent-based detection system (CaCO3/AuNPsQ), effective in the diagnosis of neuron-specific enolase (Peng et al. 2012). NPs to penetrate the blood-brain barrier (BBB) have been reported as the latest advancements in the theranostics application of neurological diseases. Lactoferrin-­ conjugated Fe3O4 NPs were developed by Qiao et  al. to pass through the BBB through Lf receptor-mediated transcytosis present in cerebral endothelial cells (Rempe et al. 2014). To the knowledge of the BBB structures, NPs are designed to facilitate the nanocarriers passing through BBB for theranostic applications in tumors like glioblastoma multiforme (GBM) reported (Karim et al. 2016). Multiple chitosan-based NPs to bind and deliver the drugs with hydrophobic and hydrophilic properties to the tumor binding site are delivered through the BBB (Fang et  al. 2015). Further, gadolinium NPs capable of permeating through BBB are used as magnetic resonance (MR) contrast mediators, enabled to uptake by parenchymal cells of brain tumor for high-resolution imaging-based diagnostics (Caro et  al. 2021). Liu et al. have synthesized BBB-penetrable NPs modified B6 peptide to form a neuroprotective peptide (NAP) loaded B6-NAP/PEG-PLA, leading to the release of NAPs helping in the better accumulation of B6-NAP/PEG-PLA compared with NPs without B6 peptide (Liu et al. 2013). Ion activities are closely linked to the brain’s physiological environment, and analyzing the brain at ion levels gives novel insights into neurological diseases (Wei

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et al. 2020). Ion-based sensors are in great demand due to the specific properties (sensitivity, selectivity, and biocompatibility) exhibited by them (Qian and Xu 2015). The effect on physiological alterations of the brain initiated by the transportation of ions through the transmembrane is analyzed based on the ion sensors (Yellen 2002). Ion sensors are applied in the diagnostics of neurological disorders (Sangubotla and Kim 2018; Yin et al. 2015) in the form of detection of reflective membrane potentials (RMP) of the ions (K+, Na+, Ca2+) in the brain (Ding et  al. 2016; Clausen 2003; Rusakov 2012; Egelman and Montague 1999). Nanosensors are also designed specifically to monitor intracellular and subcellular homeostasis. Nanosensors with good retention and stability are essential in monitoring, such as chloride ion-sensitive DNA-based nanosensors (Saha et al. 2015) and pH-sensitive assembly-based nanosensors (Feng et al. 2019), which are reported. Nanoparticles for imaging: NPs may be adopted as contrasting interpreters in medical imaging, allowing for improved visualization of tissues and organs. For example, researchers have developed nanoparticles applied in magnetic resonance imaging (MRI), enabling high-resolution imaging of tumors (Liu et  al. 2022). Nanorobots for targeted therapy: Nanorobots can be programmed to deliver drugs to specific cells or tissues, enabling targeted therapy. For example, researchers have developed nanorobots that can target and destroy brain cancer cells using a combination of chemotherapy and photothermal therapy (Aggarwal and Kumar 2022). These developments have transformed nanotechnology in medical diagnostics and therapy, providing more effective and personalized treatments for a range of diseases. The development of futuristic personalized nanomedicines based on nanomaterials for the therapeutic applications of neurological diseases is the latest trend in nanotechnology (Chaudhary 2022). Due to the higher incidence of neuroinfectious, neurodegenerative and neurocognitive disorders globally, there is a need for the development of personalized medicines to cater for the patient population who are on the edge of survival. These challenges have made it inevitable for scientists to engineer biocompatible nanomaterials-based theranostics to overcome limitations like physiochemical properties and BBB as major hurdles for conventional therapeutics. Engineered nanocarriers based on metals (gold, platinum), lipid (liposomes, lipoplexes), gels (silica, hydrogels), magnetic particles (magnetic, magnetoelectric), etc. (Nair et al. 2016) have been exploited to develop novel personalized therapeutics. These nanocarriers facilitate the physicians to deliver the desired dose of the drug release to the specific targets in the patients (Kaushik et al. 2017).

5.3 Developments in Nanotherapeutics for Neurological Diseases/Disorders Nanotherapeutics, which involves the use of nanoscale materials for therapeutic purposes, exhibits promising potential in the treatment of neurological disorders (Baboota and Ali 2020). Being an increasingly developing field, it can alter the therapeutic options currently being practiced and can enhance its key advancements

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in the field of targeted drug delivery (TDD), blood-brain barrier penetration, gene therapy, neuromodulation, neuroprotection, and personalized medicine. Some of the potential nanotherapeutics options in neurological diseases involve the following:

5.3.1 Nanoparticle-Based Target Drug Delivery Nanoparticles are drug carriers to specific target brain cells as they can easily penetrate the BBB. This technology has been applied to treat disorders like Parkinson’s and Alzheimer’s, where traditional drugs have limited success (Mohi-ud-Din et al. 2022). Nanoparticles as contrast agents for brain imaging techniques like MRI and CT scans provide better resolution and contrast. They can also be used to target specific cells or tissues in the brain for imaging (Avasthi et al. 2020). Nanoparticles have been used to promote neural regeneration and repair damaged nerve cells and in neurological disorders in the brain, such as treating spinal cord injuries (Kumar et al. 2020; Lowe et al. 2019). Nanosensors are effectively applied to monitor and detect changes in brain activity that may indicate the onset of neurological diseases. This could lead to earlier diagnosis and treatment of diseases like epilepsy and multiple sclerosis. Nanotherapeutics have several advantages over traditional drugs in treating neurological ailments. One of the key advancements is their ability to pass through the protective BBB layer. Nanotherapeutics are engineered with the potential to bypass the BBB, making the nanoparticle involved in the therapeutic delivery agents to the brain (Ghosh et al. 2022) (Fig. 5.2). This gives an edge to treat multiple infections and neurodegenerative diseases. Engineered nanoparticles are helpful in the delivery of drugs to the target across the BBB and disrupt the aggregation of beta-­amyloid plaques, the hallmark of AD (Li et  al. 2022). NPs, as drug delivery agents, can stimulate the production of dopamine, a neurotransmitter that is deficient in Parkinson’s disease. This supports alleviating some of the motor symptoms linked with the disease (Sharma et al. 2021). Nanotherapeutics are effective for targeted drug delivery applications, where nanoparticles, including dendrimers and liposomes, are developed for drug delivery specifically for certain brain sites (Table  5.1). The precision of targeted delivery reduces the adverse effects by increasing the therapeutic potential in diseases like AD and PD. NPs can be engineered to bypass this barrier and directly deliver drugs to the brain, where they can be more effective. Nanotechnology has been proven effective in the therapeutics of some of the below neurological disorders (Nguyen et al. 2021; Naqvi et al. 2020). Nanoparticles as nanocarriers can deliver drugs that suppress the immune system, which can help reduce inflammation and prevent damage to the nerves (Naqvi et al. 2020). NPs are effective delivery agents of drugs used in targeting specific tumor cells without interrupting the healthy brain cells (Naqvi et al. 2020). Nanoparticles are effective in delivering drugs that target the production of mutant huntingtin protein, which is responsible for the degeneration of neurons in Huntington’s disease (Valadão et al. 2022).

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Fig. 5.2  Engineered nanoparticles customized for specific drug delivery in the brain to penetrate the protective BBB layer to reduce off-target effects

Nanotechnology could be employed to develop more advanced brain-computer interfaces, allowing people with disabilities to control devices using their thoughts. For example, gold nanoparticles (AuNPs) have been used to deliver drugs in the therapy of glioblastoma (Hasannejad-Asl et al. 2023). An example of AuNP-based drug delivery was described by (Li et  al. 2021) about the application of brain-­ targeted gold nanoparticles (AuNPs) for drug delivery as a potential solution to AD. AuNPs can be engineered to pass through BBB and specifically target the brain regions, allowing for more effective delivery of drugs to treat AD. Curcumin, a natural compound found in turmeric, exhibits significance in the therapy of AD, displaying anti-inflammatory and antioxidant properties. However, curcumin has low bioavailability and is rapidly metabolized in the body, making it difficult to achieve therapeutic levels in the brain (Chainoglou and Hadjipavlou-Litina 2020). By loading curcumin into brain-targeted AuNPs, researchers can improve its bioavailability and enhance its ability to cross the BBB. Treatment of mouse models of AD has shown promising results. In a study, researchers used brain-targeted NPs loaded with curcumin to treat a mouse model of AD. The AuNPs were designed to target beta-amyloid plaques. The NPs were able to pass through the BBB and aggregate within the brain, where they released curcumin over time. This resulted in a significant reduction in beta-­amyloid plaques. AuNPs have been investigated for TDD in cerebral ischemia, which is a condition characterized by reduced blood flow and oxygen supply to the brain. Other reports also enhance on the investigation of the NPs to target tau proteins in AD. Ameri et  al. (2020) developed nanoparticles loaded with an antibody that

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Table 5.1  Representative nanoparticles adopted in neurotherapeutics Type of nanoparticles Magnetic nanoparticles Gold nanoparticles Chitosan-based NPs

Disease Glioblastoma, PD, AD AD, brain tumors, and PD Epilepsy, PD, AD, antipsychotic, schizophrenia

Gadolinium NPs

Orthotopic glioblastoma, brain cancers, multiple sclerosis, AD

Liposomes

AD, PD disease, glioblastoma, brain tumors, stroke AD, PD, amyotrophic lateral sclerosis, epilepsy, and intracerebral hemorrhage PD, traumatic brain injury, AD, multiple sclerosis, and amyotrophic lateral sclerosis Cellular apoptosis, AD, Aβ amyloidosis, cervical cancer, PD AD, PD, amyotrophic lateral sclerosis, glioblastoma Glioblastoma

Mesoporous silica nanoparticles Cerium oxide nanoparticles Copper oxide nanoparticles Ferric oxide nanoparticles Gold-coated nanoshells Zinc oxide nanowires Gold nanowires Quantum dots

Brain damage, AD, glioblastoma AD, PD, gliomas Prion’s disease, AD and PD

Therapeutic application Magnetic hyperthermia, targeted drug delivery Penetration of BBB, targeted drug delivery Targeted drug delivery, sustained drug release, gene therapy, permeation enhancement, to cross BBB Theranostics, penetration of BBB, enhanced permeability, multifunctional drug delivery Crossing over BBB, targeted drug delivery Enhanced drug delivery, overcoming the BBB, enhanced bioavailability, sustained drug release Neuroprotective, ameliorative, target drug delivery Enhanced drug delivery, bioavailability

Theranostic, ameliorate neurodegeneration, anticancer Brain cancer therapy, BBB penetrative, Theranostics BBB penetrative, target drug delivery, anti-cancer BBB penetrative, target drug delivery BBB penetrative, target drug delivery, neuroprotective effects

specifically targeted tau proteins and demonstrated that they could effectively reduce tau protein levels in AD mice models. Alternatively, Wu et al. (2020a) reported a study that investigated therapeutics for PD using mesoporous silica nanoparticles loaded with glial cell line-derived neurotrophic factor (GDNF) in a rat model. GDNF is a naturally derived protein exhibiting protective effects on dopaminergic neurons, which are the cells that are damaged in PD. However, delivering GDNF to the brain can be challenging due to its large size and poor ability to pass through BBB. The above study addressed the challenge by using mesoporous silica NPs (nano-carriers) for GDNF. Small-sized nanoparticles were developed to pass through the blood-brain barrier and were loaded with GDNF.  They found that the mesoporous silica nanoparticles loaded with GDNF were able to protect dopaminergic neurons in the PD rat model, leading to improved motor function. The study also showed the potential of NPs to deliver GDNF in a sustained means over a period of several weeks, which could be

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beneficial for the long-term treatment of PD. Though the use of mesoporous silica nanoparticles loaded with GDNF shows promise as a potential treatment for PD, but further research is required to validate efficacy, safety, and potential side effects in humans (Wu et al. 2020a, b).

5.3.1.1 Nanozymes Nanozymes, or nanomaterials with intrinsic enzyme-like activities, have shown great potential as therapeutics for neurological disorders based on their high stability, biocompatibility, and catalytic activity. Some of the examples of nanozyme application in nanotherapeutics of neurological disorders are discussed below. Zhang et al. (2023) reported the investigation on the use of cerium oxide nanoparticles (CeO2 NPs) as a nanozyme for the therapy of ischemic stroke in a rat model. The study showed that it could reduce oxidative stress and inflammation in the brain and enhances the therapeutic effects (Wang et  al. 2020a, b). CeO2 NPs exhibit intrinsic antioxidant and anti-inflammatory activities, making them promising therapeutic agents for neurodegenerative diseases like ischemic stroke (Yadav and Nara 2022). In this study, the researchers synthesized CeO2 NPs and characterized their size, shape, and catalytic activity. They then administered the CeO2 NP nanozymes to rats with an induced ischemic stroke. The researchers found that the CeO2 NP nanozymes were able to reduce the reactive oxygen species (ROS) production and inhibit the expression of inflammatory cytokines in the brain, which are involved in the pathogenesis of ischemic stroke. This led to reduced brain damage and enhanced neurological function in the rats (Wu et al. 2020a, b). He et al. (2022) investigated the use of copper oxide nanoparticles (CuO NPs) with superoxide dismutase (SOD) and catalase-like activities as a nanozyme for the therapy of traumatic brain injury (TBI) in a mouse model. CuO NPs exhibit to possess intrinsic SOD and catalase-like activities, which makes them a promising therapeutic agent for TBI (Wang et al. 2021). In this study, the researchers synthesized CuO NPs and characterized their size, shape, and catalytic activity. They then administered the CuO NP nanozymes to mice with an induced TBI. The researchers found that the CuO NP nanozymes were able to scavenge superoxide anions and hydrogen peroxide in the brain are identified to be involved in the pathogenesis of TBI. This led to reduced oxidative stress and inflammation in the brain and enhanced neurological activity in the mice. The potential of using CuO NP nanozymes with SOD and catalase-like activities as a therapeutic agent for TBI has been demonstrated. The intrinsic catalytic activities of CuO NPs rank them as promising NPs in the treatment of other neurodegenerative diseases as well. Further validation is essential to investigate the long-term safety and efficacy of CuO NP nanozymes. Parvez et al. (2022) developed Fe2O3 nanoparticles (NPs) loaded with edaravone, a free radical scavenger with neuroprotective properties, for the therapy of ischemic stroke in a rat model. In the study, Fe2O3 NPs with a size of ~10 nm and loaded with edaravone were prepared. They then injected the Fe2O3-edaravone NPs into rats that had suffered an induced ischemic stroke. The researchers found that the Fe2O3-edaravone NPs have blood-brain barrier crossing potential and accumulate in the ischemic region of the

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brain, leading to improved neurological function and reduced oxidative stress and inflammation in the brain. The study also showed that the Fe2O3 NPs had good biocompatibility and low toxicity, suggesting that they may be a secure and effective platform for the targeted delivery of neurotherapeutics for ischemic stroke and other neurological diseases (He et al. 2020).

5.3.1.2 Nanoshells Nanoshells (NS) are a type of NPs comprising a dielectric core with a thin metallic shell that can be used for various biomedical applications, including neurotherapeutics. The unique properties of NS, including size and surface chemistry, fit them as an attractive option for TDD and imaging. NS can be engineered for targeted delivery to these protein aggregates, delivering therapeutic agents directly to the affected cells in the therapy of for the treatment of AD and PD. NS can be used to selectively deliver chemotherapy drugs to the tumor cells to cure the brain tumor. Some of the examples of NS applications are discussed below. A recent study reported on NS describes the use of silver-coated nanoshells loaded with nerve growth factor (NGF) to cure AD in a rat model. In this study, the researchers administered the specifically designed silver-coated nanoshells loaded with NGF via intranasal delivery to target the olfactory epithelium and deliver NGF to the brain in the rat model of AD (Di Pietro et al. 2016). The study results suggest that the treatment with silver-coated nanoshells loaded with NGF improved cognitive ability and reduced the accretion of amyloid-beta plaques in the AD rat model’s brain. The researchers also observed an enhancement in the number of cholinergic neurons, which are important for cognitive function, in the treated rat’s brain. An alternative study reports the development of copper sulfide nanoshells loaded with the anti-inflammatory drug dexamethasone for the treatment of cerebral ischemia-­reperfusion injury (CIRJ) in a rat model. Cerebral ischemia-reperfusion injury takes place due to the obstruction in blood flow to the brain being interrupted and then reinstated, leading to tissue damage and inflammation. In their study, the researchers used a rat model of CIRJ and administered the copper sulfide nanoshells loaded with dexamethasone via intranasal delivery. The results showed that the treatment with copper sulfide nanoshells packed with dexamethasone reduced inflammation, improved cognitive function, and reduced the volume of brain tissue damage in the rat model of CIRJ (Wang et al. 2020a, b). One of the potential approaches for the treatment of multiple sclerosis (MS) is to use nanoshells as nano-delivery agents of immunosuppressive drugs into the affected cells directly. For example, Chen et al. (2021) reported nanoshells developed using mesoporous silica nanoparticles (MSNs) loaded with fingolimod, an immunosuppressive drug used to treat MS. The researchers demonstrated that the MSNs loaded with fingolimod had a longer circulation time and lower toxicity compared to free fingolimod, and it effectively targeted immune cells and reduced inflammation in a mouse model of MS. The above-discussed types of NS loaded with specific drugs exhibit significant potential as nanotherapeutics for the treatment of neurological disorders. However, further research is essential to optimize

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the design and quantify the safety and efficiency of these methods during the administration to patients.

5.3.1.3 Nanowires Nanowires have a unique one-dimensional structure that allows for precise control of electrical and chemical properties. They have been investigated for their potential use in various neurological disorders. A few examples are discussed below: Zinc oxide nanowires have been studied as a significant delivery agent in the therapy of AD. Zinc oxide nanowires show a high surface area, making them suitable for drug delivery applications. They can be functionalized with various molecules, including drugs, for TDD in the brain. Zinc oxide nanowires have also been shown to be biocompatible, meaning they are unlikely to cause harm or toxicity to cells and tissues in the body. Zinc oxide nanowires are an efficient therapeutic for AD (Singh et al. 2020). This study investigated the application of zinc oxide nanowires as therapeutic agents for AD.  The researchers investigated the nanowire’s potential to reduce oxidative stress and inflammation in the neural system and also inhibition of amyloid-beta plaques, which are a hallmark of the disease. The study also showed that the nanowires were biocompatible and did not cause significant toxicity in cell cultures. Gold nanowires have been explored as a potential nanotherapeutics for the therapy of PD, and a recent research on gold nanowires as an effective tool for Parkinson’s disease therapy by Batool et al. (2022) discusses the potential use of gold nanowires as a nanotherapeutic for Parkinson’s disease. The authors describe how gold nanowires as a nanotherapeutic can be functionalized with various molecules, including drugs, to target and target moieties to specifically target dopaminergic neurons distressed by PD (Batool et al. 2022). The authors also discuss the biocompatibility and safety of gold nanowires, highlighting their potential as a suitable material for biomedical applications. They review several studies that have demonstrated the efficacy of gold nanowires in improving Parkinson’s disease symptoms in animal models. 5.3.1.4 Quantum Dots (QDs) Quantum dots are semiconductor crystals present in nanoscale possessing exceptional optical and electronic properties and have been extensively explored in the therapeutics of NDs. The key advantage of QDs is their potential to pass through the blood-brain barrier (BBB), which is essential for drug delivery. This enables QDs for targeted delivery of therapeutics directly to the brain, potentially improving treatment outcomes for neurological disorders (Ghosh et al. 2022). Some studies of QD applications as neurotherapeutics are discussed below: Hu et al. used QDs conjugated with nerve growth factor (NGF) to perform the repair of ischemic brain injury in a rat model of stroke. Results showed QD-NGF treatment significantly improved neurological function and reduced brain tissue damage, compared to control groups. They suggested that QD-mediated NGF delivery may be a potential therapeutic agent for stroke (Hu et al. 2023). Further, a study on QD-based nano-delivery agents in the treatment of stroke was reported. They

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loaded QDs with the neuroprotective agent edaravone and demonstrated that the role of QDs may pass through the BBB and aggregate in the ischemic brain region. Treatment with QD-edaravone significantly reduced brain tissue damage and enhanced neurological activity in the stroke rat model (Deore et al. 2022). Alternatively, Pada et al. (2019) in their study developed a used QDs to deliver the antiepileptic drug lamotrigine (LTG) to the brain in a rat model of epilepsy. The researchers first synthesized QDs with a core-shell structure consisting of a cadmium telluride (CdTe) core and a zinc sulfide (ZnS) shell, which were functionalized with polyethylene glycol (PEG) to enhance their biocompatibility and stability (Wang et al. 2022). They then loaded the QDs with LTG and injected them into the rats intravenously. The QDs were able to cross the blood-brain barrier and accumulate in the epileptic focus in the brain. Treatment with QD-LTG significantly reduced seizure frequency and duration in the rats, compared to control groups. The researchers also examined the safety of QD-LTG treatment and found no evidence of toxicity or adverse effects on the rats’ behavior, body weight, or organ function. Despite these promising applications, there are still challenges to be addressed before QDs can be widely used in therapeutics for neurological disorders. More research evidence is needed to understand these issues and to optimize QDs for safe and effective use in neurotherapeutics.

5.3.1.5 Microfluidics Microfluidics is a rapidly developing field that has shown potential for novel therapeutics for NDs like stroke. Vashist et al. (2023) report the development of a microfluidic system that can generate oxygenated brain organoids to study the mechanisms of stroke and to screen potential therapeutics (Sayad et al. 2022). The system consists of a microfluidic chip that houses multiple chambers and channels, which can be used to culture brain organoids under controlled conditions. The researchers generated oxygenated brain organoids by exposing the organoids to a constant supply of oxygen through the microfluidic system. They demonstrated that the oxygenated brain organoids had improved cell viability and physiological relevance compared to traditional brain organoid culture methods. They then used the microfluidic system to study the effects of ischemic stroke on brain organoids and to screen potential therapeutics. They demonstrated that the oxygenated brain organoids exhibited hallmarks of ischemic stroke, including hypoxia and oxidative stress. They also screened a library of compounds for their ability to protect the brain organoids from ischemic injury and identified several potential candidates for stroke therapy. Brain-on-a-Chip platform for investigating the pathophysiology of AD (AD) is reported by Park et al. The platform consisted of a microfluidic chip that housed multiple compartments, including a neural compartment, a vascular compartment, and an extracellular matrix (ECM) compartment (Park et al. 2015). The neural compartment contained neurons and glial cells, while the vascular compartment contained endothelial cells that formed a blood-brain barrier (BBB)-like structure. The ECM compartment contained astrocytes and extracellular matrix proteins that provided structural support to the cells. Using the Brain-on-a-Chip platform, the

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researchers investigated the effects of amyloid beta (Aβ) accumulation and tau hyperphosphorylation on neuronal function in AD. They found that Aβ accumulation and tau hyperphosphorylation led to neuronal dysfunction and degeneration, as well as disruption of the BBB-like structure. They also observed that treatment with drugs that target Aβ and tau pathology, such as bexarotene and methylene blue, improved neuronal function and reduced Aβ and tau pathology in the Brain-on-a-­ Chip platform. It is a promising tool for studying the pathophysiology of AD and may provide a platform for personalized medicine and drug screening in AD therapeutics (Bang et al. 2021; Amirifar et al. 2022).

5.4 Nanotherapeutics in the Treatment of Rare Neurological Diseases Huntington’s disease: Researchers have developed polymeric nanoparticles loaded with a siRNA targeting the huntingtin gene (Fig. 5.3). The nanoparticles were able to pass through the BBB and effectively silence the mutant huntingtin gene in a mouse model of the disease (Wang et al. 2020a, b). Amyotrophic lateral sclerosis (ALS): Pichla et al. (2020) report the use of mesoporous silica nanoparticles (MSN) to deliver a cocktail of neurotrophic factors to the spinal cord of a mouse model of ALS. The nanoparticles were able to increase motor neuron survival and delay disease onset (Pichla et al. 2020). Creutzfeldt-Jakob disease: Researchers were able to analyze lipid nanoparticles loaded with a siRNA targeting the prion protein. The nanoparticles were able to effectively reduce prion protein levels in the brain of a mouse model of the disease

Fig. 5.3  Schematic illustration of the nanocarrier (cyclodextrin) for siRNA delivery to target HTT gene for targeted delivery

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(Zahir-Jouzdani et  al. 2018). Neurofibromatosis: Scientists developed polymeric nanoparticles loaded with an siRNA targeting the NF1 gene, which is mutated in neurofibromatosis Type 1. The NPs selectively delivered the siRNA to the tumors associated with the disease in a mouse model (Aigner and Kögel 2018) (Fig. 5.4). Rett syndrome: Scientists used lipid nanoparticles to deliver a siRNA targeting the MECP2 gene, which is mutated in Rett syndrome, to the brains of mice. The NPs were able to effectively reduce MECP2 expression and improve behavioral deficits associated with the disease (Palmieri et al. 2023). Spinocerebellar ataxia: Lee et al. (2020) have developed polymeric nanoparticles loaded with plasmid DNA encoding a neurotrophic factor to deliver gene therapy to the cerebellum of a mouse model of the disease. The NPs were able to increase the rate of expression of the neurotrophic factor and improve motor coordination deficits (Lee et al. 2014).

5.4.1 Nanotherapeutics in Prevalent Neuro Cancers Nanotechnology has shown great promise in the development of targeted therapies for various neurological cancers. Here are some recent advancements in nanotherapeutics for prevalent neurological cancers:

Fig. 5.4  Depiction of liposome-encapsulated delivery of siRNA. (a) siRNA is compressed into the inner water phase of liposomes. (b) siRNA complexed with liposome encompassing cationic lipids

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Glioblastoma multiforme (GBM): GBM is regarded as a grade IV brain tumor by the WHO. Researchers have developed several nanotherapeutics for GBM, including nanoparticles loaded with drugs or therapeutic agents targeting the tumor microenvironment (Fig. 5.5). A study by Ashrafizadeh et al. (2021) indicated the use of hyaluronic acid-modified NPs packed with doxorubicin for the therapy of GBM in a mouse model. Medulloblastoma (MB): MB is a malignant brain tumor, commonly seen in children. Researchers have developed nanotherapeutics for MB, including nanoparticles loaded with drugs or peptides targeting tumor cells or the tumor microenvironment. A study by Yue et  al. (2023) indicated the use of iron oxide nanoparticles loaded with a peptide targeting the cancer stem cell marker CD133 for the therapy of MB in a mouse model. Meningioma: Meningioma is a tumor that arises from the meninges of the brain and spinal cord. Researchers have developed nanotherapeutics for meningioma, including NPs complexes with drugs or peptides targeting the tumor cells or the tumor microenvironment.

5.5 Limitations of Nanotechnology in Neurotherapeutics Amidst the copious advantages of NPs exhibited in various applications of neurotherapeutics by fulfilling the pharmacokinetic parameters as effective drug delivery systems and imaging, particular limitations cannot be ignored, as most of the technologies come with disadvantages. To date, some of the collated information on the disadvantages of the NPs as neuro medicine (Hanif et  al. 2021; Hsu et  al. 2021;

Fig. 5.5  Depiction of therapeutic brain delivery strategy to treat brain cancer based on novel nanotherapeutics

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Kaur et al. 2021) indicate the limitations of nanotechnology widely in the therapy of neurological diseases. The complex procedure also involves production costs leading to concerns of affordability for multifunctional NPs reducing the cost-­ effectiveness (Cheng et al. 2021). The toxicity issues of NPs come to the fore while dealing with the treatment of neurological disorders; further, the toxic effects of NPs are directly leading to adverse immune response and inflammation are the neurotoxic effects reported in multiple clinical studies (Catalan-Figueroa & Morales. 2021). It can further cause the direct implications on structure and functional alterations in neuronal cells by interacting with glial cells by activating the series of reactions causing reversible or irreversible effects (Nikita et al. 2023). The stability and bioavailability are the further hurdles leading to the limited effect of the NPs whenever they are exposed to digestive systems and enzymes, and the varied pH, ionizability, and temperature are the major factors influencing the effectiveness of the NPs (McClements and McClements 2016; Zhang et al. 2021a, b; Ling et al. 2021).

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Role of Nanoparticles and Nanotherapeutics in the Diagnosis of Serious Zoonotic and Neurological Diseases Nida Wazir, Maria Asghar, Sahar Younis, Muhammad Ahsan Naeem, Waqas Ahmad, Qaiser Akram, and Muhammad Akram Khan

Abstract

Over the past few years, nanotechnology has emerged as a promising tool in the field of biomedical sciences for the diagnosis, treatment, and management of zoonotic diseases related to the central nervous system. Complicated pathogenesis of zoonotic diseases, blood-brain barrier, and unavailability of specified channels for drug delivery have made alternate treatment regimens more cumbersome and delayed, leading to increased prevalence of these diseases in different human and animal population settings. These zoonotic diseases also pose serious risks to global health and cause huge economic losses in developing

N. Wazir · M. Asghar University of Veterinary and Animal Sciences, Lahore, Narowal Campus, Narowal, Pakistan S. Younis Faculty of Veterinary Science, University of Agriculture, Faisalabad, Pakistan M. A. Naeem Department of Basic Sciences, University of Veterinary and Animal Sciences, Lahore, Narowal Campus, Narowal, Pakistan W. Ahmad (*) Department of Clinical Sciences, University of Veterinary and Animal Sciences, Lahore, Narowal Campus, Narowal, Pakistan e-mail: [email protected] Q. Akram Department of Pathobiology, University of Veterinary and Animal Sciences, Lahore, Narowal Campus, Narowal, Pakistan M. A. Khan Department of Veterinary Pathology, Faculty of Veterinary and Animal Science, PMAS-Arid Agriculture University, Rawalpindi, Pakistan © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_6

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countries by causing epidemics and pandemics. Nanomaterials or modified nanoformulations provide suitable prophylactic, preventive (antiviral, antibacterial, and antiparasitic), and functional outcomes to resolve chronic and acute infections. This technology has also been considered as the best alternative to antibiotics, antivirals, and antiparasitic drugs that promote resistance against viral, bacterial, and parasitic infections. These nanotherapeutics also provide timely solutions by avoiding unexpected further health risks to humans, animals, and the surrounding environment, thus ensuring biosafety in healthcare settings. Target-selected nano-materials such as metal nanoparticles, polymeric nanoparticles, nanoemulsions, liposomes, and nanocrystals are administered through various routes in animals and humans, and these nanoparticles bind or manipulate the specific cellular receptors in host cells and also guide drug molecules along the drug delivery pathways in the central nervous system. In this chapter, various currently used diagnostics and treatment regimens of nanotechnology have been discussed among different neurodegenerative diseases such as cerebral malaria, trypanosomiasis, rabies, and listeriosis. Keywords

Nanoparticles · Macrophage · Antibacterial · Antiviral · Nerve cells · Bioimaging

6.1 Introduction The emergence and spread of several zoonotic diseases are significantly influenced by the risk factors associated with humans, animals, and the environment (Thompson and Kutz 2019). Animals are the source of the majority of infectious diseases that also infect people. According to the Asia Pacific Strategy for Emerging Diseases: 2010, more than 70% of pathogens originate from wildlife species and account for over 60% of new human infections. Recent decades have seen a rise in human diseases that have originated from animals and are directly linked to meals containing animal products (Slingenbergh 2013; Thompson and Kutz 2019). Zoonotic diseases are transferred from animals to humans either directly or indirectly. The World Health Organization (WHO) defines zoonosis as any disease or infection that is naturally passable from vertebrate animals to people or from humans to animals. Approximately 61% of human pathogens are zoonotic in nature (Taylor et al. 2001). These are major public health concerns and immediate human health risks that can result in huge mortality among animals and humans. The 13 most prevalent zoonoses have had the greatest impact on poor pastoral workers in low- and middle-income countries, causing an estimated 2.4 billion cases of morbidity and 2.7 million deaths in humans per year, in addition to their harmful influence on human health (Grace et al. 2012). The majority of these diseases have an impact on animal health and reduce cattle productivity (Grace et al. 2012). The use of nanotechnology in healthcare has shown promising results in the field of selecting suitable diagnostic tools to detect and treat neurodegenerative diseases.

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There are different viral, bacterial, and parasitic zoonotic diseases with altered microscopic manifestations in the central nervous system (CNS). The viral zoonotic pathogens include rabies virus, Crimean Congo fever virus, and Influenza A virus, etc. In bacterial zoonotic pathogens, we have Brucella species, Listeria monocytogenes, Leptospira interrogans, Coxiella burnetii, Chlamydia psittaci, and Streptococcus iniae, whereas parasitic zoonotic pathogens are cerebral malaria, trypanosoma, amoeba, Toxoplasma gondii, Taenia solium, and Echinococcus species. There are also infectious prion proteins that are zoonotic in nature, affecting CNS (Goh et al. 2020). Nanotechnology is now used for the diagnosis of several infectious diseases (Ambrosi et al. 2010). Yet, one of the particles that can be employed to aid in disease diagnosis is gold NPs. These particles are excellent for studying proteins and deoxyribonucleic acid (DNA) because of their strong absorption and optic refraction of gold nanoparticles at specific wavelengths, as well as their fluorescence properties are specific to optical detection methods (Taha et al. 2023). The important characteristics of gold NPs, such as their high surface-to-volume ratio and distinguishing characteristics, have also led to the basis for a biomarker (Glor et al. 2013). Last but not least, it should be noted that gold NPs can readily bind with biomolecules such as DNA, antibodies, enzymes, and other chemicals to produce more biochemical detection signals (Glor et al. 2013). Early detection of zoonotic diseases has been found critical in reducing outbreaks because timely diagnosis allows the adoption of quick intervention for the prevention of disease spread to a larger population. It also improves public health by averting large-scale infections and decreasing the strain on healthcare systems. Due to the high expenses of medical care, lost production, trade restrictions, and animal slaughter, epidemics of zoonotic disease can have a serious negative impact on the economy. Therefore, nanoparticle (NP)-based novel methods, strategies, and diagnostic regimens prove more useful by improving the prognosis using low cheap and rapid disease treatments. In essence, zoonotic diseases can also be lowered using NP-based nanovaccines, nanosensors, and nanopore sequencing, which play a pivotal role in safeguarding human health and preventing outbreaks.

6.2 Overview of Nanotherapeutics Nanotherapeutics is the use of nanotechnology in modern medicine to generate therapeutic interventions at the nanoscale level. It entails the creation, modification, and application of nanoparticles or nanomaterials for targeted drug delivery, imaging, diagnostics, and other therapeutic applications (Mukherjee et al. 2019). These NPs, which typically range in size from 1 to 100 nm, are designed to deliver medicines, nucleic acids, or other therapeutic agents to specific cells or tissues, allowing for precise and personalized medical therapies (Farokhzad and Langer 2009). Nanotherapeutics strives to improve treatment efficacy while reducing negative effects by accurately administering therapeutic chemicals to specific cells, tissues, or organs. Nanotherapeutics also use NPs qualities, such as their small size, high surface area-to-volume ratio, and capacity to interact with biological systems at the

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1. Entry through cell membrane Nanoparticle

2. Scattering inside cell

12. Sligh toxicity to host Human brain (infected) Healthy human brain (Before Treatment) (After Treatment)

3. Mitochondrial cycle stopping 11. No exit

10. Caspase pathology

4. Karyorrhexis

5. Attach from membrane inside damage

9. ROS free radical action

6. Damage ribosome 7. Protein synthesis stops 8. Damage to ETC

Fig. 6.1  The mechanism of action of NPs. (Created in BioRender.com)

molecular level. These characteristics enable increased drug solubility (Fig.  6.1), regulated release kinetics, and targeted distribution, improving therapeutic outcomes (Mukherjee et al. 2019). Figure 6.1 shows how NPs cross the blood-brain barrier (BBB) and interact with the mitochondria and ribosomal proteins to exert their effect.

6.3 Role of Nanotechnology in Developing Innovative Medical Solutions Nanotechnology plays a pivotal role in developing innovative medical solutions by offering precise control over materials and devices at the nanoscale. This capability has advanced diagnostics, drug delivery, imaging, and other medical applications. • Drug delivery: Nanotechnology allows for the development of NPs and nanocarriers capable of encapsulating medications and delivering them to specific cells or tissues. This focused medication administration reduces adverse effects, improves drug efficacy, and enables the delivery of hitherto difficult therapies. For example, NPs like liposomes and polymer-based carriers have been intensively explored for drug delivery applications (Davis et al. 2008). • Diagnostics: Nanotechnology has enabled the creation of highly sensitive and precise diagnostic equipment. Nanoscale materials, such as quantum dots and gold NPs, can be created to identify biomarkers and diseases at an early stage (Gautam 2022). These nano-sensors allow for faster and more accurate diagnostics, which improves patient outcomes (Jokerst et al. 2011). Nanotechnology has

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resulted in the development of very sensitive and specialized diagnostic tools for illness detection, such as biosensors and imaging agents (Cui et al. 2020). Therapeutics: Aside from drug delivery, nanotechnology is being employed to create novel therapeutic procedures such as photothermal therapy and gene therapy. NPs can be engineered to carry therapeutic genes or heat-absorbing chemicals, allowing them to precisely target and treat diseases such as cancer (Cheng et al. 2014). Imaging: Nanotechnology has advanced medical imaging techniques by allowing the production of better contrast agents. For example, quantum dots and iron oxide NPs can be utilized to improve contrast in MRI and fluorescence imaging, allowing for improved visualization of tissues and biological processes (Hilderbrand and Weissleder 2010). Vaccines: Nanoparticles can function as vaccine carriers and adjuvants, thereby increasing immune responses and vaccine efficacy in animals and humans (Moon et al. 2012). Antibacterial solutions: Nanotechnology has also aided in the development of antibacterial coatings and materials which facilitate infection prevention, particularly in medical devices and implants (Mura et al. 2013). Cancer therapy: NPs can be created to specifically target cancer cells to improve cancer therapy precision. They can also improve the efficacy of medicines such as chemotherapy and radiation therapy (Dreaden et al. 2012).

6.4 Nano-Based Theranostics for Prion Diseases Prion diseases, which are also referred to as transmissible spongiform encephalopathies (TSEs), are deadly neurological illnesses that impact both humans and animals. Many transmissible spongiform encephalopathies (TSEs) affecting mammals, such as scrapie in sheep, chronic wasting disease in deer and elk, bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeldt-Jakob disease (CJD) in humans, are caused by infectious prion proteins. BSE, also known as mad cow disease, is among the zoonotic diseases that have been identified relatively recently. Reports of the initial instances of BSE emerged in the United Kingdom in 1986 (Ironside et al. 2018). Variant CJD (vCJD) is a human disorder that was initially detected in 1996 and has been connected to the outbreak of BSE in cattle. The consumption of contaminated meat and other food products that originated from infected cattle is believed to be the reason behind the development of vCJD (Tee et al. 2018). Nano diagnostics have shown enhanced sensitivity by enabling the detection of diseases even at molar concentrations to promote early detection. The application of nanomedicine in the detection of CNS diseases has the potential to offer unparalleled accuracy (Chhabra et  al. 2015). Nanotechnology offers several promising avenues for the treatment of CNS diseases, such as sustained drug release, increased bioavailability, and targeted delivery of various drug molecules. Surface modification of small molecules can also prevent in  vivo degradation. Additionally, the development of novel nanomaterials can provide groundbreaking solutions for the

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detection and treatment of prion and prion-like proteins, emphasizing the importance of accuracy in nanomedicine (Díaz-Caballero et al. 2018). • NPs Based on Drug Delivery Systems and the Blood-Brain Barrier (BBB) • Researchers have made progress in understanding the complex nature of prion disease and are working on developing effective protocols for its management. However, there is still a need for further research and clinical trials to determine the most efficient NP-based drug delivery strategies that can effectively cross the blood-brain barrier. The effectiveness of drugs and their compatibility with biological systems also remain significant areas of concern in nanotechnology that need to be addressed (Murugesan and Scheibel 2020). Delivering drugs to specific targets for neurodegenerative diseases is challenging due to the blood-brain barrier (BBB), which can limit drug passage. However, using NP-based drug delivery systems has become increasingly popular because they can improve drug absorption by increasing the surface area-to-volume ratio. This makes them a promising option for delivering drugs to the CNS. Incorporating gold NPs into a polyelectrolyte multilayer has been shown to facilitate their penetration through the BBB and reach specific regions of the CNS. This approach has demonstrated the ability to differentiate between protein aggregates, which is also useful in diagnosing prion diseases affecting the CNS. • In crafting the content of this book chapter, a deliberate focus has been placed on the inclusion of specific diseases that are intricately linked to the CNS. This strategic selection is rooted in recognition of the paramount significance of the CNS as a pivotal command center governing a multitude of bodily functions and cognitive processes. By highlighting zoonotic or neurodegenerative diseases, we endeavor to illuminate the profound interplay between neurological health and overall well-being. As these diseases affect the CNS, therefore, the therapeutic and theranostic applications are also essential to describe. Furthermore, various nanotechnology-based diagnostic and preventive strategies have been described to emphasize NPs. • Nanocarriers and Biosensors in BBB • To effectively apply nanotechnology for biosensors and molecular imaging of neurodegenerative disorders, it is crucial to consider the potential risks associated with the use of NPs (Singh et al. 2013). PEGylation has been identified as an effective mechanism for improving the ability of NPs to cross the BBB.  Nanocarriers, which can encapsulate NPs, have also shown promise in enhancing their use for diagnosis, treatment, and targeted imaging. This has led to research on the efficiency of different nano-carriers for comparative imaging at high resolution. Gold nanoparticles (AuNPs) capped with dihydrolipoic acid (DHLA-­AuNPs) have been found to be effective in detecting amyloid genic prion protein without the need for labeling. This approach has demonstrated high specificity, and the addition of NaCl has increased sensitivity (Zhang et al. 2016). • Additives and Biodegradable Polymeric NPs • Additives such as NaCl have been found to play a role in enhancing the sensitivity of NPs for detecting amyloid genic prion protein (Chaudhary et al. 2023).

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Additionally, biodegradable polymeric NPs have been shown to have benefits such as controlled release, improved bioavailability, and reduced toxicity, making them suitable for a wide range of applications, including the treatment of prion diseases (Kumari et al. 2010). Studies have also demonstrated that Nano-­ PSO can delay the onset of prion diseases. In addition, the antioxidant properties of PSO have been found to target mitochondrial dysfunction in the case of genetic CJD (Keller et al. 2019).

6.5 Different NPs to Detect Prion Proteins in BBB NPs have demonstrated promising applications for addressing prion diseases by improving BBB targeting. They are not only useful for drug delivery and diagnosis but also as a safer method for reducing oxidative damage caused by stress due to their low toxicity. Additionally, NPs have shown to be key agents in achieving high specificity and sensitivity for detecting prion diseases through the BBB. Coupling superparamagnetic NPs with protein misfolding cyclic amplification (PMCA) reactions has improved prion detection capture. This nontoxic methodology offers a promising approach for both the decontamination and detection of prions (Miller and Supattapone 2011). Iron oxide NPs have been previously used as a biosafety contrast agent in magnetic resonance imaging (MRI). In addition, the detection of prion protein has been achieved through stainless steel, which has been found to be facilitated by the presence of nickel and molybdenum (Luhr et al. 2009). In a similar study, magnetic NPs were modified by chemically adsorbing l-aspartic acid (LAA), and gold-coated NPs were carboxylated with mercaptopropionic acid. These modified NPs immobilized prion-protein complexes to study the kinetics of prion binding and also facilitated their detection. Conjugating magnetic NPs with resonator arrays in nanomechanical resonators has improved the sensitivity for ante-mortem detection of prion proteins (Varshney et al. 2008). • NP-Based Biosensors for Prion Diseases • The use of biosensors equipped with NPs demonstrated high sensitivity in detecting prion proteins, enabling rapid detection of prion diseases and improved treatment outcomes. One study utilized gold nanorods to detect amyloid fibrils in prion proteins through plasmonic chirality elicited by plasmonic NPs, offering an efficient detection method for prion diseases (Kumar et al. 2018). RNA aptamers substituted with 2-fluoropyrimidine were evaluated for their binding patterns against prions, showing high specificity and non-immunogenicity. Aptamers offered high specificity at sub-nanomolar concentrations, making them effective agents for various applications. On the other hand, NPs provided high sensitivity even at very low concentrations. In vitro detection of prions was performed using prion-binding aptamers, which induced conformational changes in the secondary structure and efficiently characterized the preparation of a reagent for prion detection. Gold-coated nanoparticles were employed to immobilize recombinant

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prion protein, and DNA aptamers focusing on PrPSc were able to achieve sensitive diagnosis (Wang et al. 2011). • Nucleic Acid Aptamers • The use of nucleic acid aptamers in combination with nanocarriers has the potential to greatly improve prion detection and diagnosis by providing high sensitivity and specificity. The binding affinity of aptamers at the interface of magnetic nanoparticles functionalized with l-aspartic acid for prion immobilization appears to be more effective than that of gold-coated magnetic nanoparticles functionalized with a carboxyl group for binding to prion protein targets (Kouassi et al. 2007). The application of DNA/RNA/peptide aptamers for prion disease detection highlights the potential of peptide aptamers in targeting and drug design, leading to effective molecular dissection and abatement strategies. Therefore, combining NPs with aptamer technology would result in significant specificity and sensitivity for detecting prion proteins (Gilch and Schätzl 2009). Small interfering RNA (siRNA) or antisense oligonucleotides, which precisely target and decrease the expression of prion proteins, can be carried via functionalized nanoparticles. The goal of this strategy is to reduce the production of pathogenic proteins (Kouassi et al. 2007).

6.6 Manipulation of NPs as Drug Carriers The NPs can be designed to encapsulate drugs and deliver them specifically to the brain, thereby increasing the efficacy and reducing the side effects of the drug. For example, one study published in 2018 demonstrated that gold NPs could be used to deliver siRNA targeting the PrP gene to the brain of scrapie-infected neurological tissue, leading to a reduction in PrP accumulation and an improvement in survival rates (Zahir-Jouzdani et al. 2018). These NPs can also be designed to mimic the structure of infectious agents, thereby triggering an immune response and generating antibodies that can target and clear the misfolded PrP protein. In one study published in 2021, researchers used viruslike particles (VLPs) to generate PrP-­ specific antibodies in scrapie-infected mice, leading to a significant reduction in PrP accumulation and an improvement in survival rates (Eiden et al. 2021). In order to improve their interaction with endothelial cells and facilitate their passage through the BBB, the NPs may use surface changes. This will increase the number of drugs delivered to the CNS. Oxidative stress is linked to the pathophysiology of prions. Antioxidant-loaded NPs can prevent oxidative damage, potentially slowing the progression of illness and neuronal degeneration (Vashist et al. 2023).

6.7 Nanotherapeutics for the Diagnosis of Rabies Rabies is a severe neurological disease that causes terrifying death in all age groups (Royal et al. 2023). Mass vaccination and population control are the most economical and effective ways of preventing rabies in dogs (Bansal et al. 2019). Rabies virus

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is a lipid-coated, enveloped RNA virus that causes the terrifying neurological disease, which is known as rabies. It belongs to the Rhabdoviridae family and the Lyssavirus genus (Ahmad et al. 2021). Infection with the canine variant of the rabies virus produces horrifying neurological symptoms and tragic death if the essential post-exposure prophylaxis (PEP) is not carried out after a bite injury from a rabid dog (Singh and Ahmad 2018). Therefore, timely diagnosis of rabies is important for humans and animals that could avoid serious mortality rates in both species. One of the diagnostic approaches is enlisted in Table 6.1, in which the rabies virus diagnosis has been exhibited using organic NPs (Kerry et al. 2019). Similarly, Fig. 6.2 shows the details regarding rabies protection and immunocontraception are also provided using an adjuvanted hydrogel-based pDNA nanoparticulate vaccination (Figs. 6.2 and 6.3). This vaccine has the advantages of being inexpensively produced, less labor-intensive, stable at room temperature, relatively safe, and capable of inducing both humoral and cellular immune responses (Bansal et al. 2019). Figure 6.3 shows the mechanism by which nanoparticulated rabies vaccine may help to control the population of free-roaming dogs that cause dog-bite injuries to humans and animals leading to rabies.

6.8 Possible Nano-Based Approach for Nipah Virus (NiV) Diagnosis The zoonotic Nipah virus (NiV) infection is caused by a Henipavirus from the Paramyxoviridae family. The disease’s progression can be fatal and highly serious (Bruno et  al. 2022). Nipah is named after a Malaysian village called Kampung Sungai Nipah, where the first outbreak of this disease was observed in the years 1998–1999. The non-segmented RNA genome of the paramyxovirus Nipah is composed of helical nucleocapsids and possesses negative-stranded polarity (Banerjee et al. 2019). It is an emerging virus that can lead to fatal encephalitis and severe respiratory illnesses in people. The Pteropus genus of frugivorous bats known as “flying foxes” serves as the virus’s primary natural reservoir (Bruno et al. 2022).

Table 6.1  Diagnosis and inhibition of rabies virus using an organic nano-based approach (Kerry et al. 2019) Nanoparticles Polymeric NPs Chitosan-PEG (polyethylene glycol) nanoparticles Dendrimer G2 dendrimer, nonlinear globular

Bioactive substance Attenuated viral antigen from rabies

Organism simulation –

PEG-600 (polyethylene glycol 600) with citric acid

J774A.1 cell-line and NMRI mice

Mechanism of action Effective and long-lasting immune system elicitor with low toxicity –

Objective Immunization

Efficacy of adjuvanticity

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Fig. 6.2 A structural representation of pDNA-based NPs rabies vaccine. (Created in BioRender.com)

NiV is among the priority viruses on the WHO’s priority list that are likely to cause epidemics and require prompt research and development (Aditi and Shariff 2019). The present invasion in the domains of nanoscience and virology has opened up a new avenue for the rapid diagnosis of viruses. A hybrid nanosystem can bind the NiV virion’s two spiking glycoproteins (G) and fusion protein (F), RNA, and capsid proteins such as nucleo-capsid proteins (N), phosphoproteins (P), and large polymerase proteins (L). For the detection of NiV, a colorimetric viral detection assay that takes use of the peroxidase-like activity of gold nanoparticle-carbon nanotubes (AuNPs-CNT) nanohybrid can be created (Kerry et al. 2019). In vitro evaluation of a nano-based method for inactivating NiV using reactive oxygen species (ROS) or a photothermal media is possible. Viral binding to the host cell surface receptor can also be suppressed by preventing viral binding of gp120 and Clusters of Differentiation 4 (CD4) attachment. The ability of NPs to bind with G and F proteins of NiV makes them interesting candidates for use as viral entry inhibitors. Another method for preventing the entry of the NiV is to activate AKT, phosphorylate p53, and prevent the accumulation of ROS caused by the virus. Although NPs’ effectiveness as an antiviral agent against NiV has not yet been assessed, it can be roughly hypothesized that these studies are direct depictions of

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Fig. 6.3  Immunocontraception by pDNA nanoparticulate rabies vaccine: Immunocontraception is achieved by targeting gonadotrophin-releasing hormone (GnRH), a neuronal hormone secreted in the hypothalamus and transported to the anterior pituitary via the hypothalamic–pituitary portal system. After binding to the receptor, GnRH stimulates the production and release of pituitary hormones, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), which play a key role in genital development and reproduction. Antibodies against GnRH prevent its binding to the receptor and thus inhibit the secretion of FSH and LH to achieve sterility. This cascading affects the maturation of ovarian follicles or spermatogenesis to achieve immunocontraception (Bansal et al. 2019). (Created in BioRender.com)

the likelihood that NPs hold tremendous potential as an antiviral agent against NiV, as shown in the accompanying Fig. 6.4 (Kerry et al. 2019).

6.9 Use of NPs to Detect Listeriosis Listeria monocytogenes also cause serious neurological disease by the bacterium called Listeria monocytogenes. It results from contaminated food and water. Although listeriosis has a modest incidence rate (1%), it has a significant fatality rate (30%) (Kasalica et  al. 2011). The gram-positive, rod-shaped, flagellate, catalase-­ positive, and non-spore-forming bacteria is a facultative intracellular pathogen that causes major neurological infection in different species of animals and humans (Nightingale et al. 2004; McLauchlin et al. 2013; Falardeau et al. 2021). The disease further causes septicemia, meningitis, encephalitis, and abortion, as shown in Fig. 6.5. The L. monocytogenes infection cycle in humans is depicted schematically. After eating tainted food, bacteria cross the intestinal barrier and enter the circulation. The

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Fig. 6.4  NPs’ possible role in NiV pathogenesis at various phases: (A) Preventing membrane fusion and early viral attachment during the viral invasion; (B) infected cell NiV-G protein interaction with healthy cell Ephrin B2/B3 was inhibited, and NiV-G protein’s activated C-terminus region promoted NiV-F activation; (C) activation of AKT; (D) activation of p53 phosphorylation; (E) blocking of viral transcription, translation, and replication; (F) transcription of viruses is altered (Kerry et al. 2019). (Created in BioRender.com)

Fig. 6.5  Infective cycle of Listeria monocytogenes showing encephalitis, abortion, and septicemia

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organism circulates through the portal circulation to the liver and spleen, where it multiplies before spreading throughout the bloodstream. The organism then infects the brain and fetus of a pregnant woman (Sibanda and Buys 2022). A quick and trustworthy method for the simultaneous detection of L. monocytogenes that can be found in food products. In this method, the target bacterial cells were separated using immunomagnetic separation (IMS) based on magnetic nanobeads (MNBs). Propidium monoazide (PMA) was used to selectively inhibit the DNA detection from dead cells in order to identify only the living bacteria (Yang et al. 2013).

6.10 Use of NPs to Detect Toxoplasmosis An obligate intracellular parasite called Toxoplasma gondii (T. gondii) affects a wide variety of species, including around one-third of all people on the planet (Skariah et al. 2012). There are significant regional differences in the prevalence of T. gondii infection (Robert-Gangneux et al. 2012). Prevalence is modest and ranges between 10% and 30% in North America, Southeast Asia, and Northern Europe. A worrisome number of 80% has been reported in some areas of tropical Africa and Latin America, whereas a modest prevalence of between 30% and 50% is documented for Central and Southern Europe (Robert-Gangneux et al. 2012). Millions of people in the United States are infected with this parasite, which is also listed as a neglected disease and requires immediate preventive measures (Ben-Harari et al. 2019). It is outside the diagnostic range of ELISA since various antibody titers are observed at various illness stages, and serum levels of marker proteins are often relatively low in the early stages of most diseases. Because of this, several of the common ELISA techniques have not been shown to be successful at various stages of the disease (Glor et al. 2013). Toxoplasmosis diagnosis has not yet been improved by research on the creation of a nano-enzyme-linked immunosorbent assay (Nano-ELISA).

6.11 Use of NPs to Detect Trypanosomiasis Trypanosoma is a parasite that causes trypanosomiasis, a serious public health disease in the rural areas of the world. The parasite causes two types of trypanosomiasis, which are commonly called African trypanosomiasis (sleeping sickness) and American trypanosomiasis (Chagas disease). Trypanosomes have a full life cycle that includes both mammalian hosts (people and animals) and insect vectors (tsetse fly and triatomine bugs). The use of very few medications in the treatment of trypanosomiasis has been approved. Additionally, there are significant drawbacks in existing trypanocidal therapy, including ineffectiveness, harmful side effects, and drug resistance. Tropical parasite infection has always been disregarded by researchers and medicine producers because there are no financial benefits associated with it. More inventive and effective approaches are desperately needed to reduce the

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number of deaths brought on by these diseases. With a many-fold reduction in doses, NP-based medication has demonstrated a significant improvement in efficacy (Prayag et al. 2020). For the targeted delivery of anti-trypanosomal medicines, passive targeting and active targeting are the two methods that are based on nanotechnology. Passive targeting uses conventional and PEGylated nanocarriers, while active targeting dispenses ligand-anchored nanocarriers. Passive nanocarriers rely on the physicochemical characteristics of the nanocarriers along with their anatomy, physiology, and pathophysiology (Zhang et al. 2018). Infected cell-specific or parasite-­ specific ligands might be conjugated to the surface of nanocarriers to facilitate active targeting of cargo-loaded nanocarriers that permit improved drug accumulation at the target region (Yamashita and Hashida 2013; Muro 2012).

6.12 Use of NPs to Detect Cerebral Malaria Malaria is caused by Plasmodium falciparum, which causes the most prevalent neurological profile, cerebral malaria. The patients who survive these types of injuries may lead to long-term neurocognitive disorders (Idro et al. 2010). To better interact with infected red blood cells (RBCs) and parasite membranes, a nanocarrier’s ability to stay in the bloodstream for an extended period of time is its most crucial characteristic in causing the infection (Mosqueira et al. 2004). The capacity to be surface-modified by conjugation of particular ligands, cell-adhesion capabilities, and protection of unstable medicines are further intriguing properties (Kayser and Kiderlen 2003; Date et  al. 2007). The two main methods to deliver intravenous antimalarial medications targeting infected erythrocytes and, on occasion, hepatocytes are through the use of nanocarriers. These nanocarriers use passive and active targeting. Traditional nanocarriers, such as liposomes and hydrophobic polymeric nanoparticles, are used for passive targeting (Barratt 2003) or long-circulating nanocarriers with surface modifications (e.g., PEGylated) (Vauthier and Couvreur 2007; Lasic et al. 1995; Gref et al. 1995). On the other hand, active targeting is accomplished using nanocarriers that possess modified surfaces having particular ligands, such as proteins, peptides, polysaccharides, or antibodies (Barratt 2003).

6.13 Use of NPs to Detect Naegleria fowleri Due to several high-profile instances, Naegleria fowleri has received a lot of media attention over the past 5 years. The eukaryotic, free-living amoeba N. fowleri is a member of the Percolozoa phylum. Naegleria amoebae are common in the environment and can be found in soil and freshwater bodies, where they feed on bacteria and enter the human brain via the nose. Although primary amoebic meningoencephalitis appears to be rather uncommon compared to other infections, N. fowleri infection is a serious neurological disease and almost usually fatal (Grace et al. 2015).

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Various medicines were conjugated with various NPs and tested against free-­ living amoebas since NPs are thought to increase medication effectiveness. Guanabenz was conjugated with silver and gold NPs in an earlier work. Significant amoebic activity of the conjugated drug against N. fowleri and Acanthamoeba castellanii was already discovered (Lee et al. 1979). Additionally, it was discovered that the effects of the medications against A. castellanii and N. fowleri were enhanced when Diazepam, Phenobarbitone, and Phenytoin were conjugated with silver NPs (Seidel et al. 1982).

6.14 Current and Future Potential of Nanotherapeutics to Control Neurological Diseases Control and prevention of neurological infectious diseases are difficult because they include complex transmission channels involving vectors like insects or animals. The BBB prevents medications from entering the brain, which reduces the efficacy of conventional therapies for treating neurological infections (Alyautdin et  al. 2014). A variety of pathogens and symptoms make up neurological zoonotic diseases that need specialized preventive strategies for each pathogen and its associated neurological condition (Chaudhary 2022). Due to difficulties in delivering NP-based therapies to the brain to focus on particularly affected regions, conventional medications frequently fail to effectively treat neurological infections (Lee et al. 2013). Drug-resistant strains can emerge from the extended use of existing antibiotics, decreasing the efficacy of therapies over time. Infected brain regions can be carefully targeted using NPs, minimizing harm to healthy tissues and improving treatment effectiveness. Through receptor-mediated transcytosis or other transport pathways, NPs have the ability to break through the BBB, allowing for effective medication delivery to the brain. Combinatorial treatments are made possible by the versatility of different types of NPs (lipid-based, polymer-based, etc.) in encapsulating various therapeutic ingredients (Walvekar et al. 2019). Nanotherapeutics regulate the release of drugs inside the afflicted brain regions, improve drug concentration, and minimize systemic side effects. The development of drug-resistant strains can be halted by maintaining the efficacy of treatment and encapsulating a mixture of medications inside NPs (Sinah and Sehgal 2022). By assisting in the early diagnosis and precise monitoring of neurological infections, MPs can be used as diagnostic instruments to enable prompt intervention. Based on genetic and disease-specific characteristics, nano-therapeutics can be tailored for individual patients, resulting in more effective and focused treatments.

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7

Drug Delivery for Neurological Disorders Using Nanotechnology Sagnik Nag, Mahek Bhatt, Subhrojyoti Ghosh, Anuvab Dey, Srijita Paul, Shrestha Dutta, Sourav Mohanto, B. H. Jaswanth Gowda, and Mohammed Gulzar Ahmed

Abstract

The central nervous system (CNS) is imperative in maintaining a homeostatic balance between the mind and the physiological state of being. Any form of physical or biological impairment demonstrating a deteriorating nervous system condition is characterized as neurological disorders (NDs), primarily comprising S. Nag Pharmacology Unit, Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Bandar Sunway, Malaysia M. Bhatt Department of Life Sciences, School of Arts and Science, Ahmedabad University, Ahmedabad, Gujarat, India S. Ghosh Department of Biotechnology, IIT Madras, Chennai, Tamil Nadu, India A. Dey Department of Biological Sciences and Bioengineering, IIT Guwahati, North Guwahati, Assam, India S. Paul Department of Microbiology, Gurudas College, Kolkata, West Bengal, India S. Dutta Department of Chemistry and Chemical Biology, Indian Institute of Technology, Dhanbad, Jharkhand, India S. Mohanto (*) · M. G. Ahmed Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to be University), Mangaluru, Karnataka, India B. H. Jaswanth Gowda Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to be University), Mangaluru, Karnataka, India School of Pharmacy, Queen’s University Belfast, Belfast, UK © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_7

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neurodegenerative, immunogenic, neuro-muscular, trauma-induced, neuropathic, and psychological ailments. Conventional medications and nonspecific therapeutics available in the market either suppress the  symptoms or delayed the disease progression rate. However, nothing has yet been developed to eradicate symptoms and revert to normal cerebral conditions. The conventional strategies have low efficacy and show limited mitigation of symptoms due to their inability to cross the blood-brain barrier (BBB). Since the dawn of materials sciences, nanotechnological interventions have been catering to fabricate biocompatible nanoformulations and actualize alternate drug delivery platforms, which specifically target prominent disease biomarkers associated with NDs, with limited toxicological implications. The drugs can also be nano-engineered to be delivered across the blood-brain barrier and perform specific functions. Therefore, this chapter tends to deliberate current understanding and recent findings on existing drug delivery routes and platforms using nanotechnological interventions. The chapter discusses challenges with nanomedicines developed for NDs and suggests personalized therapeutics as a solution. Keywords

Neurological disorder · Drug delivery · Nanotechnology · Nanoparticles · Personalized medicine

7.1 Introduction The central nervous system (CNS) is an intricate system of nerves, tissues, and biological compartments that communicate to control the body’s physiological and mental functions; any impairment or damage to the CNS can lead to neurological disorders. The term neurological disorders (NDs) refers to a range of conditions that impact the central and peripheral nervous systems. These medical conditions cause major changes in an individual’s behavior, cognitive, and physical ability, resulting in a decrease in their overall standard of life. Post subsequent pandemics and epidemics of SARS-CoV2, monkeypox virus (Chatterjee et al. 2023) and others, the healthcare management system has taken a back, and treatment of chronic diseases like NDs, diabetes (Ghosh et al. 2023), and cancer was neglected for a lot of time (Neekita et al. 2023). The prevalence of NDs is increasing rapidly, with estimates suggesting that over one billion people suffer from various forms of neurological disorders globally. NDs can be classified into several categories, including neurodegenerative, immunogenic, neuro-muscular, trauma-induced, neuropathic, and psychological disorders, among others. The frequency of neurological conditions such as dementia, particularly as the population ages, and the prevalence of neurological diseases such as dementia, alzheimer’s disease, multiple sclerosis (MS), Parkinson’s disease, and primary brain tumors is rising (Riggs 2001; Ashique et al. 2023). Recent estimates place the neurological disorders as part of the Global Burden of Disease (GBD) Study—including migraine, tension-type headaches (TTH), and medication-overuse headaches (MOH), as well as Alzheimer’s disease along with other dementias, multiple sclerosis, Parkinson’s disease, and epileptic seizures—at

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3% of the global disease burden. Dementia, migraine, epilepsy, and stroke are among the 50 most prevalent causes of disability-adjusted life years (DALYs) despite what could appear to be a tiny overall percentage (Thakur et al. 2016). NDs are caused by a variety of factors, including genetic abnormalities, environmental exposure, and aging. Furthermore, most of the current therapies are symptomatic and incapable of improving quality of life or delaying or ameliorating damage (Masoudi Asil et al. 2020). Stroke, which causes significant impairment and ultimately the loss of brain cells, is the world’s third-largest cause of death and is the second-most prevalent health issue in the United States after Alzheimer’s disease (Ding et  al. 2020). Neurodegenerative illnesses are significantly more likely to develop as people age. The majority of research indicates that in the coming decades, a large portion of the population will likely be affected by neurodegenerative diseases, highlighting the need to look into their root causes and develop novel approaches for their early detection, prevention, and treatment. There are currently no specific therapies that can successfully reverse or cure NDs, and traditional drugs simply provide temporary comfort or halt the progression of the condition. This is mostly due to most medications’ inability to cross the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) (Masoudi Asil et al. 2020). The BBB serves as a barrier to keep toxins, microbes, parasites, viruses, and other blood-borne diseases out of the brain. In order to provide the brain with the best environment possible, it also works to transport nutrients and regulate the passage of fluid and ions (Teleanu et al. 2022). The BBB and BCSFB are critical barriers that govern molecular transport between the blood and the CNS. The BBB is made up of endothelial cells that line the blood arteries in the brain, whereas the BCSFB is made up of specialized cells in the choroid plexus. Both of these barriers prohibit numerous therapeutic molecules, including medications, from entering the CNS, making it difficult to successfully treat NDs (de la Torre and Ceña 2018). Drug delivery systems that utilize nanotechnology have emerged as a viable method for the treatment of NDs. These systems entail the creation of biocompatible and biodegradable nanoparticles capable of transporting medications to specific CNS targets while minimizing toxicity and side effects. These nanoparticles can be modified with targeted ligands that specifically attach to receptors on CNS cells, allowing therapeutic compounds to be delivered to specific cells and regions. Since nanomaterials (NMs) are used for medical treatments in a variety of ailments, including neurological issues, nanomedicine is a growing field and is acknowledged as one of the most versatile and potentially effective drug delivery techniques in hard-toreach places, including the brain. New technologies such as nanoparticles (NPs), nanotubes, nanomedicines, nanocarriers, microparticles (MPs), and polymer NMs have tremendously profited from advances in nanotechnology. These advancements make it possible to precisely transport medications to their intended molecular targets and sites of action, which helps in the management of neurodegenerative diseases (Siddiqi et  al. 2018). The continuous release characteristics of nano-drug delivery devices enhance the controlled and safe diffusion of loaded medication, reducing the dosing schedule. The adaptability of created NMs is what attracts researchers, particularly in the biological field. In particular, their physical characteristics can be used for the purpose of tissue engineering and regeneration as well

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as for diagnosis or therapy. Chemical functionalization could also provide them with targeted selectivity. There are at present only a few viable therapies for neurodegenerative illnesses and a spectrum of NDs (summarized in Table 7.1), despite the huge quantity of published data and established results, and additional research is needed to elucidate the processes causing neurological disorders (Kanwar et al. 2012).

Table 7.1  Various conventional therapeutics associated drawbacks and mode of delivery in neurological disorders (NDs) Mode of delivery Continuous infusion, or as intermittent injections

Drug Apomorphine

Target ND Parkinson’s disease

Benzodiazepine

Seizure

Oral drug delivery

Fenfluramine

Dravet syndrome

Oral drug delivery

Nimodipine

Oral drug delivery

Carbapenems

Aneurysmal subarachnoid hemorrhage Meningitis

Dimethyl fumarate

Multiple sclerosis

Acyclovir

Drawback The most frequent adverse responses at the injection or infusion sites include bruising, subcutaneous nodules, and, rarely, necrosis or abscess development, followed by nausea and somnolence Drowsiness, light-­ headedness. Confusion. It can also lead to withdrawal issues Reduced appetite, loss of weight, sedation, fatigue, elevated blood pressure, and mood swings, perhaps including suicidal thoughts Dizziness, light-­ headedness, or fainting

Oral drug delivery or intravenous injection Oral drug delivery

Antimicrobial resistance

Viral encephalitis

Intravenous

Levadopa

Parkinson’s disease

Intravenous injection

Riluzole

Amyotrophic lateral sclerosis

Both oral and intravenous drug delivery

Extreme tiredness, irregular heartbeat, easy bruising/bleeding High daily dosage and delayed onset of therapeutic benefits at least 1–2 months Mouth numbness, difficulty falling asleep or staying asleep

Significant decrease in T cell population

Reference Carbone et al. (2019)

Kanner and Bicchi (2022) Hakami and Tahir Hakami (2021) Neifert et al. (2020) Mancuso et al. (2021) Jordan et al. (2022) Said and Kang (2022) Siddiqi et al. (2018) Chiò et al. (2020)

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7.2 Nanomaterials and Drug Delivery for Neurological Disorders (NDs): Gaps and Prospects For the efficient treatment of NDs, gaps still need to be filled in spite of the substantial advancements in nanomedicine. The incomplete knowledge of the processes that govern the passage of nanoparticles over the BBB is one of the primary problems. Also, various approaches have been proposed, such as surface modification, magnetic targeting, and ultrasound-mediated delivery. Additionally, it’s important to thoroughly assess the safety of nanomedicines to prevent any possible toxicological repercussions. It’s also important to think about how nanoparticles can affect the CNS in the long run and how they might leave the body. The lack of particular biomarkers for NDs, which impedes the development of focused nanomedicines, is another significant obstacle. Additionally, it is necessary to create individualized nanomedicines that can address the special characteristics of each patient’s ND. The ability to provide NPs characteristics like the viability of integrating both hydrophilic and hydrophobic medicines, as well as the ability to be delivered via a range of administration including oral, inhalational, and parenteral, makes them even more tempting for medical purposes (Petkar et al. 2011). It is crucial to keep in mind that systemic injection of NPs causes significant changes while developing them for therapeutic applications (Deng et al. 2020). Decreased adverse effects, extended blood circulation, and improved medication stability, bioavailability, and targeting effectiveness are only a few of the benefits of nanomaterial drug delivery (Shi et al. 2014). The ability to transport imaging agents, medications, and ligands with targeted properties simultaneously via adaptable nanocarriers is also advantageous for monitoring drug distribution, triggering drug release when exposed to an external stimulus, such as a beam of laser light, temperatures, as well as an ultrasonic sound, and conceptually detecting potentially harmful drug accumulation (Thukral et al. 2023). With careful design, the functionalization might facilitate nanocarriers’ passage through the BBB and enable appropriate BBB penetration. The use of endogenous and exogenous specialized ligands and substrates through interaction with unique transporters or receptor-mediated transcytosis on the BBB has considerably improved BBB crossing enabling brain-­ targeting administration (Gao 2016). For instance, transferrin, lactoferrin, glucose, polysorbate 80, and anti-TfR antibodies have shown considerable efficacy in boosting BBB penetration and brain distribution of nanocarriers as brain-targeting ligands. BBB permeability modulators can be loaded onto nanocarriers and functionalized with the goal of regulating the diffusion of drugs via the paracellular barrier, stopping active efflux, or using adsorptive-mediated transcytosis, respectively (Han et  al. 2016; Yang et  al. 2018). In order to treat brain illnesses, novel medication delivery methods that can penetrate the BBB are available in Table 7.2.

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Table 7.2  Various biogenic and inorganic nanocarriers used for targeting various NDs using specific drug conjugates in specific cases Nanomaterial Exosomes

Drug conjugate Coenzyme Q10

Target ND Alzheimer’s disease Parkinson’s disease

Microbubble– liposome complex

Liposome

Ultrasound-­ responsive neurotrophic factor Paclitaxel

Liposome

ApoE2 gene

Lipid nanocarrier

Selegiline

Microemulsion

Carbamazepine

Exosomes

Silibinin

Micelles

Nanozyme

Gold NPs

–

Graphene NPs

–

Liposome

SPIONs conjugated with anti-CD20

PLGA-NPs

Doxorubicin

Central nervous system lymphoma Glioma

PCL-NPs

Indomethacin

Glioma

Lipid nanoparticles

Edelfosine

Glioma

Cerium oxide NPs

Cerium oxide

Carbon NPs

Drug delivery vehicle model

Amyotrophic lateral sclerosis Brain stroke

Solid lipid nanoparticles (SLNs) Solid lipid nanoparticles (SLNs)

Rosmarinic acid Dimethyl fumarate

Glioma Alzheimer’s disease Parkinson disease Epilepsy Alzheimer’s disease Parkinson disease Alzheimer’s disease Brain tumor

Huntington’s disease Multiple sclerosis

Mode of delivery Intravenous delivery Intravenous delivery via tall vein

References Sheykhhasan et al. (2022) Lin et al. (2020)

Intravenous delivery Intravenous delivery Oral drug delivery Trans nasal delivery Intravenous delivery Intravenous delivery Intravenous delivery Subcutaneous and intravenous delivery Intravenous delivery

Peng et al. (2018) Arora et al. (2020) Qamar et al. (2021) Acharya et al. (2013) Huo et al. (2021) Brynskikh et al. (2010) Siddiqi et al. (2018) Mukherjee et al. (2020)

Intravenous delivery Intraperitoneal injection Oral drug delivery

Gelperina et al. (2010) Bernardi et al. (2009) EstellaHermoso De Mendoza et al. (2011) DeCoteau et al. (2016)

Oral and intravenous delivery Subcutaneous and intravenous delivery Nasal delivery Subcutaneous administration

Saesoo et al. (2018)

Mukhtar et al. (2020) Bhatt et al. (2014) Bevilacqua Rolfsen Ferreira da Silva et al. (2022)

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Fig. 7.1  Different drug delivery routes to the human brain for therapeutic alleviation of several neurological ailments

7.3 Drug Delivery Routes for NDs In the field of drug delivery science for NDs, several promising advancements are being explored and hold great potential for the future. One area of active research is the development of noninvasive drug delivery methods that can bypass the BBB and deliver therapeutics directly to the brain. Figure 7.1 and subsequent sections shall discuss the different delivery routes for therapeutics across the BBB.

7.3.1 Invasive Method There are numerous options for delivering medications through parenteral methods, which bypass the digestive system. One such method is intrathecal administration, which allows for attaining therapeutic drug levels in the brain through invasive techniques. This approach can be achieved either directly or indirectly. Direct administration involves the utilization of an intracerebroventricular (ICV) port. This port is surgically implanted under the scalp and connected to the ventricles through an outlet catheter. By accessing the cerebrospinal fluid (CSF) within the ventricles,

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medications can be directly delivered to the brain, allowing for precise targeting of the therapeutic agent. Indirect administration, on the other hand, involves injecting medications into the subarachnoid space of the spinal cord in the lumbosacral region. This method is referred to as intrathecal lumbar (IT-L) injections. By injecting medications into the CSF surrounding the spinal cord, they can reach the brain indirectly and exert their therapeutic effects. Both direct ICV administration and indirect IT-L injections are valuable techniques for delivering medications to the central nervous system. They are particularly useful in situations where systemic administration of drugs may be ineffective or result in unwanted side effects. These methods allow for enhanced drug concentration in the brain while minimizing exposure to the rest of the body (Cohen-Pfeffer et al. 2017). ICV devices have found application in administering medications for treating various neurological ailments, encompassing lysosomal storage disorders, mucopolysaccharidosis, spasticity associated with cerebral palsy, and opioids employed in pain management. These methods have an advantage over systemic enzyme replacement therapy (ERT) in that they permit the transfer of more enzymes to the brain and, consequently, do not necessitate significant therapeutic drug dosages. These alternatives also deal with the problems brought on by the short half-lives of currently available medications while avoiding systemic exposure and toxicity problems. Moreover, ongoing clinical trials are underway to explore this approach’s potential in addressing amyotrophic lateral sclerosis (ALS) and Huntington’s disease (Rinaldi and Wood 2017; Roovers et  al. 2018). Convection-enhanced delivery (CED) encompasses a minimally invasive surgical technique that involves the careful exposure of the brain, followed by the precise insertion of one or more catheters or micro-infusion pumps with small diameters into the parenchyma. This sophisticated approach allows for the administration of therapeutics without being limited by a molecular weight cutoff, thereby ensuring a consistent and sustained presence of therapeutic concentrations across the intended target tissue (Ferguson et  al. 2014). Furthermore, the application of such invasive interventions possesss significant challenges when it comes to diseases characterized by a prolonged prodromal phase, such as alzheimer’s disease (Baizabal Carvallo et al. 2012).

7.3.2 Noninvasive Method The treatment of numerous severe neurological disorders often necessitates the utilization of large molecules, therapeutic peptides, inhibitors, or other types of drugs, as they exhibit a more favorable response compared to small-molecule therapies. This recognition stems from the fact that many of these debilitating conditions do not exhibit significant improvement with conventional small-molecule treatment approaches (Kreuter 2004). Chemically altering small molecule medications into a more lipophilic analog is a typical method to increase their BBB penetration, as demonstrated by adding a methyl group to morphine to form codeine, which yields a tenfold increase in BBB permeation. The distribution of drugs can be impeded by lipidation, a process that renders the molecule susceptible to rapid elimination from

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the bloodstream through efflux transporters. Therefore, achieving an optimal balance in drug lipidation is a delicate undertaking. Alternatively, modifying the drug’s structure can enhance its affinity for endogenous transport proteins present in the endothelium, offering an alternative strategy to facilitate its distribution. Glycation or glycosylation after the Maillard reaction may enhance peptide and drug delivery. After the Maillard reaction, glycosylation or glycation may boost biological stability while improving drug and peptide transport to the brain (Elmagbari et al. 2004). A specialized antibody that targets the transferrin receptor has been combined with EGF (a signaling molecule that binds to specific EGF receptors in brain cancer) or BDNF (a component involved in neural growth), resulting in multifunctional compounds capable of binding to the transferrin receptor at the blood-brain barrier. These compounds act as carriers, transporting peptides across the vascular wall and facilitating their distribution to the brain (Sharabi et al. 2019). To successfully transport undamaged molecules to the brain, it may be necessary to utilize enzymatically intact (pro) drugs. Various modifications such as cyclization, halogenation, methylation, PEGylation, or the introduction of non-natural bonds might be employed to ensure the integrity of the molecules during the transport process (Egleton and Davis 2005). Carrier-mediated transcytosis (CMT) has been used to transport molecules with shapes that resemble the natural substrates of different carrier proteins. Levodopa and Gabapentin are examples of this, as they have structural similarities to phenylalanine and are transported via the L-type amino acid transporter (LAT1). Furthermore, chemically altering pharmacologically potent substances can make them substrates for these endogenous carriers (He et al. 2018). Similarly, the anti-Aβ single chain antibody, doxorubicin, and paclitaxel chemotherapeutic medicines have been delivered using glutathione-functionalized, PEGylated liposomes (Agrawal et al. 2017). Receptor-mediated transcytosis (RMT) is a very particular BBB transport pathway that carries specific macromolecules from the luminal side of the endothelial cells into the brain before recycling the receptor. The effective clearance of Aβ pathology in mice has been demonstrated by conjugating the transferrin receptor antibody (TfR) with either an anti-Aβ or anti-BACE1 antibody. This approach demonstrates the potential of targeted antibody conjugation for facilitating the elimination of Aβ aggregates. Additionally, another strategy explored the use of GDNF-loaded liposomes in a rat model of Parkinson’s disease (PD) (Niewoehner et al. 2014).

7.3.3 Alternative Routes Various strategies for transporting a viral vector across the BBB exist. The first approach involves transcytosis, where the vector passes through brain vascular endothelial cells by interacting with specific receptors. The second method involves a temporary disruption of the BBB (Smith et al. 2016), allowing the vector to travel through the paracellular route and reach the interstitial areas of the CNS. The viral delivery technique leverages the inherent ability of viral vectors to infect cells with genetic material efficiently. Several viruses, including AAVs, simian virus 40,

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lentiviruses, and helper-dependent adenovirus, have been engineered as vectors for CNS administration. In the past, viral vectors had to be directly injected into specific locations in the brain using stereotaxic techniques. However, advancements have been made with AAV variants such as AAV-PHP.eB and AAV-PHP.B. These variants have shown remarkable results in enhancing CNS delivery by 40-times when administered systemically in mice. They achieve a homogeneous distribution throughout the brain tissue, providing a noninvasive option for delivering genes to the central nervous system (Bors and Erdö 2019). One approach to creating a targeted and highly concentrated pathway for vector transduction involves temporarily disrupting the BBB using magnetic resonance-guided focused ultrasound (Terstappen et al. 2021). Recently, it has become more promising to penetrate the BBB by receptor-mediated transcytosis. These approaches can be classified into three groups: utilizing a viral vector that naturally has the ability to cross the blood-­ brain barrier (commonly AAV9 (Choudhari et al. 2021)), modifying vectors to bind with specific transcellular transport receptors, and engineering vectors to target specific transcellular transport receptors (Pulgar 2019). Intranasal delivery is a practical and efficient noninvasive technique that relies on the brain’s connections to the trigeminal and olfactory nerves in the nasal mucosa (Hanson and Frey 2008). Although the BBB was bypassed using invasive delivery methods (such as intracerebroventricular), these approaches are impractical for human application due to several issues, including accessibility, safety, and expense. Neurotrophins (like nerve growth factor or FGF), neuropeptides (like insulin or interferon), cytokines, plasmids, genes, and chemotherapeutics can all be delivered by intranasal administration. Catalase, a potent antioxidant in exosomes released by monocytes and macrophages, has been reported to effectively concentrate in the brain after being administered intravenously (Haney et  al. 2015; Pramanik et  al. 2021). Furthermore, clinical studies to investigate intranasal insulin administration in Alzheimer’s disease are now underway, despite limitations in the clinical design of this research impeding further investigation (NCT02462161 and NCT03857321). The trigeminal pathway has recently been identified as a contributor to IN distribution to the CNS, particularly to caudal brain areas and the spinal cord. Growing research shows that IN infusion of neurotrophins is a noninvasive way of delivering neurotrophins to the brain to treat neurodegeneration. NGF therapy decreased neurodegeneration and enhanced cognitive function in a mouse model of Alzheimer’s disease (De Rosa et  al. 2005). The intranasal administration of IGF-I alleviated neurological impairments and brain damage in a rat stroke model. In addition, the promotion of brain neurogenesis in the subventricular zone was observed when mature mice were administered an intranasal (IN) injection of FGF-2. The neurotrophic factor associated with IN activity, along with its functional peptide fragment known as NAP, has demonstrated significant effectiveness in mitigating neurodegeneration, tau pathology, amyloid buildup, and memory decline in animal models exhibiting symptoms of Alzheimer’s disease. Phase II clinical trials are currently underway to assess the potential therapeutic benefits of intranasal (IN) NAP in individuals with alzheimer’s disease and moderate cognitive impairment. However, the administration of drugs through the nasal route presents various challenges.

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Additionally, drugs can undergo degradation due to the presence of mucosal enzymes like cytochrome P450, proteases, and peptidases (Jin et al. 2003).

7.4 Nano Drug Delivery Approaches Targeting NDs 7.4.1 Biogenic Nanomaterials Biogenic nanomaterials have demonstrated promising outcomes as drug delivery systems for the therapeutic management of neurological diseases. These nanostructures have distinct advantages over conventional drug delivery methods since they are made from biological sources such as proteins, peptides, lipids, carbohydrates, and nucleic acids (Chaudhary et  al. 2023). Exosomes’ innate biocompatibility, which relates to their low lethality and good tolerance in human systems, is a significant benefit. The central nervous system’s sick cells or tissues can be particularly targeted by biogenic nanoparticles that can be created and manipulated. These nanomaterials can be steered to the intended location of action by having their surfaces functionalized with particular ligands or antibodies, which increases the effectiveness and efficiency of drug delivery (Bandala et  al. 2020). Furthermore, therapeutic compounds like small chemicals or nucleic acids can be enclosed in and shielded from clearance and degradation by biogenic nanomaterials, improving their long-term stability and bioavailability. The use of biogenic nanoparticles has the potential to deliver medications and treatments to the brain and spinal cord, opening up promising opportunities for the cure of a wide range of neurological disorders (Mughal et al. 2021).

7.4.1.1 Exosomes Exosomes are microscopic, single-membrane, secretory organelles that closely resemble cells in appearance and have a size ranging from about 30–200 nm. These are present abundantly in specific proteins, fats, nucleic acids, and glycoconjugates. Exosomes, extracellular vesicles that affect cellular actions, are taken in by many cells (Mandal et al. 2023). To achieve targeted medication delivery, therapeutics, like tiny molecules and nucleic acid treatments, can be included in exosomes and distributed to particular cell types or tissues. Although it necessitates the creation of plasmids and the amplification of the proteins in the source cells, genetic engineering of exosomes is a relatively accessible technique for the demonstration of bioactive ligands on the exosomal membrane (Liang et al. 2021). The ability of exosomes to improve the stability of their contents while in circulation ensures that their payload has a long-lasting therapeutic effect. These nanovesicles have higher BBB penetration and are non-immunogenic, allowing for efficient uptake by target cells (Fig.  7.2). Exosomes are a better choice because synthetic BBB transporters are quickly removed by mononuclear phagocytes when administered systemically. The FDA-approved cell sources are still needed for the generation of clinical-grade exosomes, and reliable techniques are required to separate and purify exosomes, which can be labor- and time-intensive (Colao et al. 2018).

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Fig. 7.2  Strategies for targeted delivery of therapeutic exosomes to the brain. (a) Targeted delivery of exosomes to the brain can be achieved by labeling various targeting moieties on the surface of exosomes. Therapeutic exosomes can be engineered to express various targeting moieties via chemical modifications, such as click chemistry, or via genetic modification of exosome-producing cells to express targeting peptides fused with exosomal membrane-associated components, such as Lamp2b and tetraspanins. (b) RMT can be used to transport exosomes to the brain via labeling of targeting peptides on the surface of exosomes. (Reproduced with permission from Choi et  al. (2022), licensed under CC BY 4.0)

Exosomes show beneficial effects on AD by eliminating Aβ and retaining neuronal functioning. Neurofibrillary tangled structures and neurotic deposits, each made up of hyperphosphorylated tau proteins as well as Aβ oligomeric peptide, develop in the brains of people with Alzheimer’s disease (AD). These oligomers serve as carriers for the spread of Aβ-peptides among neurons. This result lends credence to the idea that the exosomal transport of Aβ peptides across neurons is responsible for their progressive buildup outside of cells. On the other hand, the downregulation of certain other proteins can reduce exosome synthesis. As a result, the transfer of Aβ-oligomers between neurons has stopped, and the toxicity that goes along with it has decreased. The most prevalent neurological condition affecting the aged worldwide is AD, and treating it is still challenging. Consequently, it is crucial to create a reliable system for drug distribution that can deliver the medication to its location successfully. Exosomes have the ability to transport exogenous gene-based payloads and drugs in addition to their inherent therapeutic potential as a result of their varied signaling capabilities in immunotherapy and regenerative medicine (Stanimirovic et al. 2018). Exosomes from the brain can cross the blood-brain barrier, demonstrating their tissue-specific nature. However, they can also have their surface altered to increase absorption, offering a viable route for administering drugs that target the brain and the spinal cord (Alvarez-Erviti et  al. 2011). Nanocarrier-based drug delivery techniques have a lot of potential for getting medications into the brain. In Alzheimer’s disease, several stages of clinical trials are

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investigating some innovative drug delivery mechanisms for anti-Alzheimer medicines (Bahadur et al. 2020). In a recent study, alpha-synuclein and curcumin were successfully loaded into exosomes produced using human endometrial precursor cells. This study’s main goal was to look at ways to make curcumin more successful at getting across the blood-brain barrier and treating Parkinson’s disease, a neurodegenerative disease. The exosomes, known as hEnSCs EXOs-Cur, were characterized, and it was discovered that they had the proper size, shape, stability, and sustained release characteristics. These novel exosomes’ ability to pass through the BBB improve motor coordination issues, inhibit the buildup of alpha-synuclein, and prevent neuronal cell death was demonstrated through in  vivo studies involving behavioral, immunohistochemical, and molecular evaluations (Mobahat et  al. 2023). Huntington’s disease, a hereditary neurological illness brought on by anomalies in the CAG repeats of the huntingtin gene, is treated by exosomes. Exosomes may be used to treat Huntington’s disease, according to several studies that have been done, one of which used glioblastoma exosomes. Exosomes have also been used by researchers as a medicinal delivery method in the management of this degenerative illness. The findings of the most recent research provide important new information about the exosome administration of miRNA for the treatment of neurodegenerative disorders. Exosomes are considered possible diagnostic indicators for several neurodegenerative brain illnesses (Shetgaonkar et al. 2022). Ataxia caused by an autosomal dominant gene prevails in the form of spinocerebellar ataxia type 3 (SCA3). The ATXN3 gene, which gives ataxin-3 species their poisonous qualities, contains an excessive amount of the trinucleotide CAG, which is the source of the disease. However, there is still a lack of an easy delivery method to the cerebral cortex despite the promising therapeutic outcomes of RNA interference technology (Rufino-Ramos et al. 2023).

7.4.1.2 Liposomes and Lipid Nanoparticles Lipid nanoparticles (LNPs) are acquiring recognition as promising means of administration for a variety of therapeutic drugs. Liposomes are spherical, nanoscale particles with a hydrophilic center surrounded by multiple bilayers of lipids (Fig. 7.3). Liposomes are undoubtedly one of the finest lipid nanoparticles for medication delivery. Lipid nanoparticle-containing respiratory compositions, such as solid lipid nanoparticles (SLNs) and nanostructured lipid carrier particles (NLCs), have demonstrated encouraging outcomes in a number of indications, including the treatment of gliomas and ailments of the cognitive system, such as seizures, sclerosis, dementia, AD, and PD (Ansari et al. 2022). In order to effectively treat disorders of the CNS, like seizures, AD, dementia, multiple sclerosis, cancers of the brain, and others, there is an increasing interest in the idea of avoiding the barrier between the brain and blood through nasal routes. Lipid nanoparticles are utilized as nanocarriers to optimize targeting to the brain, achieve sustained release, and protect against enzymatic breakdown (Costa et al. 2021). The potential of lipid nanoparticles for treating neurological illnesses has increased by their inherent capacity to permeate the brain. When thinking about current therapy options for Parkinson’s syndrome (PD), when dopaminergic neurons are deficient, supplementation of dopamine is

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Fig. 7.3  Schematic representation of liposomes. (Reproduced with permission from Nsairat et al. (2022), licensed under CC BY 4.0)

required. A dopamine-conjugated albumin/PLGA nanoparticle has been studied in a recent experiment. The nano complexes displayed permeability into the cortex and effectively penetrated the BBB. It was attributable to the albumin-coated nanoparticles (NPs), which improved their interactions with particular cell membrane receptors. Also, dopamine reduced effects in a mouse model compared to mice given l-DOPA or control NPs lacking dopamine (Jagaran and Singh 2022). The L-DOPA is typically taken via mouth because it is patient-friendly; however, it’s poorly absorbed systemically, leading to ineffective drug delivery. l-DOPA is packed in liposomes to maximize (indirect) targeting, lower systemic levels, protect against rapid breakdown, and lead to prolonged drug release. Researchers developed procedures for liposomes’ production, characterization, and l-DOPA loading. This study illustrates the simulation of l-DOPA persistence dynamics within liposomes in pertinent biological contexts that mimic in situ circumstances as an extension of ongoing research. Due to their biocompatibility and capacity to transport pharmaceutical chemicals, both aqueous and lipid-soluble ones, through the bloodbrain barrier (BBB) and into neurons, liposomes serve a critical role in the administration of nanoparticle medications. The use of liposomal vesicles for medication delivery in the treatment of neurological illnesses is crucial, according to research. The antioxidant curcumin has been shown to be pharmacologically efficient against bacteria, cancer, fungus, inflammation, and Alzheimer’s disease. Tacrine hydrochloride, an anti-Alzheimer’s drug, was administered nasally using multifunctional liposomes, examined the intravenous (IV) delivery of deuterium-­labelled cholesterol liposomes as a substitute strategy for delivering lipoprotein to the brain’s neurons as a potential treatment for Huntington’s disease (Nam et  al. 2018). Through IV administration, the formulation was effectively delivered to the brain, resulting in detectable drug levels that lasted for at least 72 h. Deuterium-­labeled cholesterol

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liposomes showed increased plasma presence after acute IV treatment, with levels increasing homogeneous production. Despite the provided dosage being three times more than the expected human intake in the context of treating subarachnoid hemorrhoids, preclinical research showed that the formulation did not exhibit any toxicity. The research teams of the authors have recently accomplished the synthesis of CSMHA that demonstrates higher adhesion to the mucosal surfaces. The CSMHA was also used to create novel mucoadhesive nanoparticles for the intranasal administration of the live, attenuated Japanese encephalitis vaccine and intravesical delivery of doxorubicin. As a result, the polymer may offer hope for oral drug delivery (Sahatsapan et al. 2022).

7.4.1.3 DNA and Protein Nanostructures In recent years, there has been an increase in neurological disorders, and the main challenge in treating such diseases is the presence of the blood-brain barrier (BBB). Last few years, researchers have studied that DNA is utilized as a tool to deliver drugs in different biomedical applications because it allows it to alter its shape and size. New shreds of evidence reveal that tetrahedral framework nucleic acid (tFNA), a unique DNA nanodevice due to its special properties like the flexibility to penetrate, receptiveness toward biological regulation, and accurate programmability, has paved the way to treat NDs (Li et al. 2021). Multiple sclerosis (MS) disease damages the axon, forms multiple demyelinating lesions, removes the oligodendrocytes, and forms inflammatory infiltrates. Studies reveal that oligodendroglia progenitor cells from IFN-ϒ treated cell death in vitro are released because of the action of proteins associated with mitochondrial apoptosis-like caspase 3, bcl-2, and bax and 250  ×  10−9  M tFNA.  Evidence shows that tFNA augments remyelination and enriches the myelinated axons by increasing the levels of myelin-associated proteins like MBP and downregulates apoptosis in the corpus callosum area (Chen et al. 2021). Recent studies reveal that although adult brain cells are damaged, they can still come back to their embryonic state, which can help to re-establish their function. These findings attract researchers to explore a new path and design more efficient therapeutic approaches to treat neurodegenerative disorders (Siafaka et al. 2022). The biological molecules are administered via intramuscular injections or subcutaneous delivery to cross the physiological barriers easily with clinical benefits. The targeting of gene delivery and protein is interesting, but the approach is complex and expensive. Genes and recombinant proteins like growth factors, and monoclonal antibodies can act pharmacologically on genetic and metabolic disorders (Miliotou et al. 2021). FDA has allowed numerous monoclonal antibodies like brain Bevacizumab for brain cancer and Natalizumab for MS (Zarini-Gakiye et al. 2020; Zeng et al. 2023).

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7.4.2 Metallic and Inorganic Nanomaterials Inorganic NPs are primarily created using metal ions (Al, Cu, Au, Fe, Pb, Ag, Cd, Co, and Zn) and metal oxide, which metal-based NPs are made using destructive or constructive processes by metals with a nanometric size. Contrary to metal-based inorganic NPs, oxidizing metals make metal oxide-based inorganic NPs produce oxides such as titanium oxide (TiO2), aluminum oxide (Al2O3), iron oxide (Fe2O3), magnetite (Fe3O4), silicon dioxide (SiO2), cerium oxide (CeO2), and zinc oxide in the presence of oxygen (ZnO). The key reasons for synthesizing metal oxide NPs are their improved efficiency and reactivity (Heuer-Jungemann et al. 2019). Due to their distinct physicochemical properties, adaptable and straightforward manufacturing methods, relatively simple surface-functionalization, and excellent biocompatibility, inorganic nanoparticulate drug-delivery systems have been the subject of much research in the last two decades. Numerous investigations have been carried out on versatile inorganic-based nanoparticles (NPs) with diverse architectures. These studies have explored the utilization of receptor-specific ligands to facilitate drug transport across the blood-brain barrier (BBB) via receptor-mediated transcytosis. Various abundant receptors within the BBB can be targeted using this approach, including transferrin receptors, insulin receptors, low-density lipoprotein receptors, and others, such as leptin receptors. These findings highlight the potential of ligand-based strategies to enhance drug delivery across the BBB. A polymeric chain and doping metal ion are just a few examples of chemical events that may easily change the surface area and activity of these NPs, which are also of their quiet properties (Das et al. 2020).

7.4.2.1 Metal and Metal Oxide NPs According to research, some metallic NPs can act as ROS scavengers. In in vivo experiments, platinum nanoparticles were observed to exhibit a notable capacity for scavenging free radicals and exerting antioxidant effects. These effects were attributed to the nanoparticle’s ability to efficiently scavenge superoxide anions and hydrogen peroxide (Takamiya et al. 2012). Platinum NPs have a substantial electron density on their surface due to their favorable surface area-to-volume ratio. This characteristic enables them to effectively quench both superoxide anions and hydrogen peroxide. Similarly, cerium oxide NPs, utilized as metal coatings to mitigate oxidation, also exhibit properties for scavenging reactive oxygen species (ROS). Notably, cerium oxide nanoparticles show promising potential as a new treatment for stroke, as they have demonstrated significant protection of adult rat spinal cord neurons. In a mouse hippocampal brain slice model of cerebral ischemia, Estevez et  al. reported (Estevez et  al. 2011) that cerium oxide nanoparticles effectively reduced ischemic cell death. These findings highlight the potential of cerium oxide nanoparticles in mitigating the detrimental effects of oxidative stress and ischemic injury. The reversible binding of oxygen and the capability of cerium NPs to transition between Ce4+ and Ce3+ states in response to oxidizing and reducing conditions play a crucial role in their ability to scavenge ROS. The Ce4+ species on the NPs surface effectively dismutase’s the superoxide radical, converting it into hydrogen

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peroxide. Subsequently, the hydrogen peroxide undergoes disproportionation, resulting in the formation of molecular oxygen and water. Moreover, both cerium and yttrium oxide NPs exhibit antioxidant properties and can reduce existing pools of ROS in HT22 cells. These characteristics underline the potential of cerium and yttrium oxide NPs in mitigating oxidative stress and maintaining cellular homeostasis. Thus, metal or metal oxide nanoparticles can potentially be novel therapeutic agents for ischemic brain oxidative injury (Schubert et al. 2006). Since the beginning of the area a few decades ago, research on biomedical nanotechnological platforms has focused heavily on gold nanoparticles (AuNPs). Because of their unique chemical, physical, electrical, optical, and biological characteristics, AuNPs are very beneficial in theranostic medicine. Due to their size, biocompatibility, and in vivo and ex vivo stability, AuNPs are particularly appealing carriers for utilization in drug-delivery applications. AuNPs may be produced in various forms, including spherical, rodlike, and cubic, among others, with diameters ranging from 1 nm to more than 100 nm, depending on the technique of synthesis (Kong et al. 2017) (Fig. 7.4). Most significantly, their versatility in functionalization sets gold NPs apart from other nanotechnological drug delivery methods. The negatively charged surface of AuNPs makes it possible to functionalize them with various biomolecules, including DNA, peptides, proteins, or antibodies. AuNPs can be functionalized in one of two ways. First, a tightly bound and stable complex is created via a covalent connection between the surface of the NPs and the functionalizing moiety; this is most frequently accomplished using a functional group that contains sulfur, such as a thiol. The non-covalent adsorption of the decorator through electrostatic interactions, hydrophobic trapping, and van der Waals forces is the second method for functionalizing AuNPs. Multiple studies have provided evidence that gold nanoparticles (AuNPs) hold promise in traversing the BBB effectively. In the context of Alzheimer’s disease therapy, Prades et al. conducted research where they introduced AuNPs conjugated to the β-sheet breaker peptide LPFFD, which was modified with a cysteine (C) residue at the N-terminus (AuNP-­CLPFFD). These AuNPs were combined with THRPPMWSPVWP (THR), a peptide known to target transferrin receptors (TfR). This innovative approach demonstrates the

Fig. 7.4  Modifications of AuNPs in a wide verity. (Reproduced with permission from Hammami et al. (2021), licensed under CC BY 4.0)

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potential of utilizing AuNPs conjugated with specific peptides to enhance the delivery of therapeutic agents across the BBB, particularly for the treatment of Alzheimer’s disease (Kandimalla et al. 2023). Due to THR’s ability to interact with TfR, which is widely distributed in the endothelial cells of the BBB, it is hypothesized that the THR-AuNP-CLPFFD NP complex can cross the BBB through RMT (Choudhari et  al. 2021). Regarding the size-dependent toxicity of functionalized gold nanoparticles, conflicting results have been reported in a number of investigations. Their size and form have historically been proven to have varied degrees of effect on toxicity (Strachan et al. 2020). Magnetic nanoparticles (MNPs) can be targeted using traditional active-targeting methods (RMT or AMT) or by applying an external magnetic field that focuses on the target location and localizes the NPs there. The MNPs can serve as drug delivery systems offering improved control over drug release and the ability to visualize their presence using MRI for diagnostic purposes. However, as the depth within the body increases, the control over the localization of nanoparticles decreases, requiring the reliance on external magnetic forces to guide them toward the desired therapeutic target. Consequently, limited clinical studies have been conducted on MNPs due to the challenges associated with their precise positioning within deeper tissues (Adams et al. 2016). Still, MNPs targeted with an external magnetic field are distinct in that they may be “dragged” across the BBB utilizing said magnetic force. Several distinct MNP types have been investigated, and many have produced findings that merit more research.

7.4.2.2 Carbon Nanotubes (CNTs) Carbon nanotubes (CNTs) are cylindrical nanostructures made of carbon with one or more layers that serve as a basis for differentiation into single-walled or multi-­ walled CNTs (Cao et al. 2023). These NPs made up of carbon are useful in various biomedical applications (Fig.  7.5). CNTs have both their pure and modified (by different polymers) forms assessed. Nanotube-neural hybrid networks can facilitate synapse development, network connectivity, and neuronal activity. A new idea for using these carbon-based NPs in designing and producing nervous tissue via cellular simulation is presented by maintaining the interaction between CNTs and stem cells (Saeedi et al. 2019). In a study by Kafa et al., an animal model examined the permeability of single-walled carbon nanotubes (SWCNTs) functionalized with amino groups using a scanning electron microscope. The researchers observed a notable accumulation of these nanostructures in brain tissue and uptake by astrocytes. Interestingly, they also noted that as the temperature increased, the permeability of these nanostructures to the brain decreased, indicating the involvement of an energy-dependent mechanism in drug delivery systems (Kafa et al. 2015). 7.4.2.3 Quantum Dots (QDs) QDs are special nanoparticles with several potential uses as therapeutics for different neurodegenerative illnesses. When utilized in nanoparticles, QDs have unique qualities, including sensitivity and selectivity. Several studies on using QDs in detecting and treating AD have been reported. QDs’ capacity to traverse the BBB

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Fig. 7.5  Examples of bioactives conjugated through carbon nanotubes. (Reproduced with permission from Kesharwani et al. (2015), copyright 2015, Elsevier)

has been demonstrated, although additional research on their potential toxicity is still needed (Mukherjee et al. 2020). The distinctive optical characteristics of QDs also contribute to their extensive usage in biological applications. Yet, QDs have drawn much attention recently because of their possible toxicity. In this instance, neurotoxicity rises when QDs are dispersed in large quantities throughout the nervous system. However, the interactions between QDs and the nervous system’s cells and tissues remain unclear. The neurotoxicity, evident in test animals, is caused by oxidative stress, elevated cytoplasmic Ca2+ levels, autophagy, which harms in vitro neural cells, impairment of synaptic transmission, and loss of plasticity (Wu et al. 2016). QDs have special optical capabilities since they are light-emitting nanocrystals in nanoscale shapes and resistant to bleaching due to the fluorescent light’s many wavelengths. QDs can therefore be used for medication administration and to view the structures of the brain and the processes underlying their activities (Utkin 2018). Furthermore, despite mounting evidence linking the pathophysiology of Parkinson’s disease to the buildup and spread of -synuclein (-syn) aggregates in the midbrain, no anti-aggregation drugs have proven effective in treating the condition. Graphene quantum dots (GQDs) prevent from fibrillating and interact with mature fibrils directly to cause their disaggregation. Moreover, GQDs can treat mitochondrial dysfunctions and inhibit the transfer of -syn disease caused by -syn-produced fibrils from neuron to neuron. GQDs can cross the BBB in vivo and guard against behavioral impairments, Lewy body/Lewy neurite pathology, and dopamine neuron death brought on by -syn preformed fibrils. Further research focused on GQDs as labeling agents for stem cells since they exhibit less cytotoxicity. The GQD treatment had no discernible effect on the human brain stem cells’ survival, metabolic

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activity, proliferative capacity, or capacity for differentiation. Furthermore, endocytosis has been used to transport GQDs into brain stem cells (Lin et al. 2020). For NPC and other associated illnesses, GQDs may offer interesting therapeutic options. The application of graphene oxide quantum dots (GOQDs) as nanozymes has demonstrated their effectiveness in reducing ROS and hydrogen peroxide (H2O2) levels in PC12 cells induced with 1-methyl-4-phenyl-pyridinium ion (MPP+), surpassing the performance of larger graphene oxide nanosheets. Furthermore, GOQDs have shown the ability to attenuate apoptosis, -synuclein accumulation, and mitochondrial damage in zebrafish subjected to MPP+ treatment. These findings highlight the potential of biocompatible GOQDs to improve human health by mitigating neurotoxicity and alleviating oxidative stress signals (Mukhtar et  al. 2020). To overcome the limitations associated with toxic heavy-metal-­ based  QDs, silicon nanocrystals offer promising advantages in terms of superior imaging capabilities. Extensive research has been conducted on the biocompatibility of SiQDs, but a seamless transition from small-animal clinical trials to large-­ animal clinical studies remains unclear. In the context of intravenous administration, both mice and monkeys were administered SiQDs along with FDA-approved materials in nano-construct form. The results of these studies revealed no observable toxicity in terms of behavior, blood parameters, or body mass in either species when administered at a dose of 200 mg/kg. However, it was noted that after 3 months of therapy, significant amounts of silicon accumulated in the liver and spleen of mice, while no silicon was detected in monkeys. This suggests the drug formulation did not undergo effective biodegradation in the monkey subjects. Another study focused on carbon dots (CDs) and showed their potential benefits for medicinal applications, including brain tumor therapy, bio-imaging, and the management of neurodegenerative illnesses (Tang et al. 2022). The BBB is a physiological barrier that prevents blood-borne chemicals from entering the central nervous system. Delivering medications and active ingredients over the BBB is one of the scientists’ major problems. Thus, it is crucial to create new tools and techniques to tackle this problem to diagnose and cure brain disorders. According to research, bio-conjugated and functionalized QDs provide excellent fluorescence probes and nano-vectors for transmission over the BBB in treating brain tumors and other disorders (Wu et al. 2016). Previous research has predominantly focused on neurons rather than glial cells, utilizing photoluminescent QDs with a CdSe core, a ZnS shell, and a compact molecular ligand coating (CL4) carrying a negative charge. In contrast, recent scientific investigations have shifted their attention to understanding the factors influencing selective delivery, specifically in neurons. The delivery of the cell-membrane-penetrating chaperone lipopeptide JB577 (WG(Palmitoyl)VKIKKP9G2H6) to individual cells in neonatal rat hippocampal slices has been enhanced using three different zwitterionic QDs coatings that vary in regions of positive or negative charges, along with a positively charged (NH2) polyethylene glycol (PEG) coat. The results of these studies have supported the preferential uptake of the lipopeptide in neurons while demonstrating a lack of uptake in glial cells, which can be attributed to the negatively charged patches on the surface of the QDs. Based on these findings, researchers have suggested incorporating green fluorescent protein (eGFP-His6) into

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hippocampal slices to promote the uptake of the lipopeptide in neurons, as it was found ineffective in astrocytes and microglial cells (Colao et al. 2018). Another in vivo investigation utilizing graphene-quantum dots (GQDs) in NPC found that these GQDs have low long-term toxicity and may be disregarded since they can penetrate the BBB Via expressed interactions, the GQD-based therapy reduces the accumulation of cholesterol in the lysosome. Selenium-doped carbon quantum dots (Se-CQDs) have been successfully used to effectively reduce secondary damage in TSCI after more research revealed their capacity to reduce reactive oxygen species. Results in astrocytes and PC12 cells showed Se-CQDs to have excellent biocompatibility and a notable protective effect against H2O2-induced oxidative damage (Cao et al. 2023).

7.4.2.4 Nanoformulations Nanogels are networks of nanoscale polymers, such as polyethylene amine and PEG, polyacrylic acid and pluronic, or other ionic or non-ionic chains, and makeup nanogels. The hydrogel NPs are unique drug delivery technologies because they concurrently exhibit hydrogel and NPs features. These nanogels’ high loading capacity (40–60%), uncommon for other NPs, is their key benefit. Transferrin and insulin surface modifications on nanogels improve BBB dispersion (Sultana et al. 2020). In vivo experiments have shown that nanogels enhance the absorption of oligonucleotides in the brain while reducing their uptake in the liver and spleen. This highlights the potential of nanogels as a promising approach to selectively target and deliver oligonucleotides to the brain while minimizing their distribution to other organs (Vinogradov 2004). Azadi et al. developed nanogels attached to the endothelial cells of the brain capillaries after being injected into the circulation and linked to apolipoproteins and then diffused into the endothelial cells by endocytosis (Azadi et al. 2012). Nanoemulsions, also known as nanosized emulsions, are stable single-phase mixtures of two liquids that are typically immiscible. Nanoemulsions exhibit thermodynamic stability and offer a versatile approach to the delivery of various substances. The size range of the droplets is 20–200 nm. Because of their kinetic stability, nanoemulsions may be created using high-energy techniques and with fewer quantities of surfactants. By delaying first-pass metabolism and boosting transport across the blood-brain barrier, nanoemulsions increase bioavailability. These advantages include targeted drug delivery, increased drug loading, improved poorly soluble drug solubility, regulated drug release, and protection against chemical or enzymatic degradation (Olivier 2005).

7.5 Challenges Associated with Nanoparticulate Drug Delivery Systems There are numerous approaches for implementing nanoparticle-based drug delivery in different sectors of applications, and each of them has its challenges. The main issue with nanoparticles is their physical instability, which causes them to agglomerate in dry conditions and gradually lose their unique nanoscale features,

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hampering the pharmaceutical drug development. By choosing the right stabilizer or stabilizer combinations from the range of surfactants, amino acids, proteins, dendrimers, polymers, plant extracts, and cryoprotectants, researchers have discovered the stability of nanoformulations has been enhanced (Sultana et al. 2020). Nowadays, polymeric nanocapsules are used as an alternative nanotechnology drug delivery technique. Nevertheless, there are some disadvantages, like the thickness evaluation of polymeric shells and the risk of harmful effects in clinical applications from residues of organic solvents. Due to their tendency to agglomerate in aqueous suspension and be unstable, nanocapsules might cause contents to leak. For the creation of functional polymeric nanocapsules, new polymeric materials, surfactants, and chemical components have been used to match market demands. It has increased prospects but also obstacles to the benefit of polymeric nanoparticles as systems for drug delivery (Liang et al. 2021). For the production of diagnostic and therapeutic medications intended to treat neurological illnesses, particularly neurodegenerative diseases and brain malignancies, achieving adequate biocompatibility and targeting effectiveness represents some of the most difficult hurdles. Nanodiamonds (NDs), a novel class of carbon-based nanomaterials, show promise in overcoming these difficulties. NDs are a viable remedy because of their chemical inertness, high biocompatibility, prolonged photostability, low toxicity, and capacity for surface modification (Tang et al. 2019). Hence, it is possible to create in vivo and in vitro monitoring devices to determine and analyze the dose and its consequences in real time. Systemic toxicity decreases, and personalized therapy is feasible due to this efficient medication delivery technology (Strachan et al. 2020). Pharmaceutical nanotechnology is currently having difficulty targeting specific diseased cells directly, yet nanoengineered particles, such as nano drugs, can penetrate the BBB and lessen invasiveness. Because of their distinctive features, such as biocompatibility, durability, low antigenicity, and high biodegradability, liposomes, polymeric NPs, and solid-lipid nanoparticles (SLNs) have all received considerable attention as noninvasive materials for drug administration to the brain. When discussing “technology,” words like “neurodevelopmental disorders,” “disease modelling,” “Alzheimer’s,” and “Parkinson’s” are regularly mentioned; however, when discussing “application,” phrases like “pathogenesis,” “drug discovery,” and “neurogenesis” are usually spoken. This shows that the research on the course of brain diseases and the creation of therapeutic strategies have both benefited from the use of brain organoid technological advances (Cao 2022). Metallic NPs can escape or cross the blood-brain barrier to enter the central nervous system and cause neurotoxicity. The brain can get harmed by astrocyte or microglial malfunction, contributing to the neurodegeneration found in Parkinson’s and Alzheimer’s disorders (Huang et al. 2022). One of the most prevalent types of dementia is Alzheimer’s disease (AD), which can start when amyloid (Aβ-42) peptides oligomerize. SnO2 NPs enhanced Aβ42 fibrillogenesis and increased amyloid oligomers/protofibrils cytotoxicity, according to several biophysical and biological investigations. The fibrillation of Aβ-42 peptides has been significantly accelerated by SnO2 NPs, which also promotes the generation of more harmful species (Jaragh-Alhadad and Falahati 2022). According to specific research, AgNPs are mutagenic and genotoxic, and the

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severity of their effects is inversely related to AgNPs size and directly dependent on NP dose. General toxicity, including genotoxicity, can be affected by coating agents required for stabilizing NPs in a solution (Ivlieva et al. 2022). There are a number of critical areas when it comes to the neurotoxicity of nanoparticles where more study is required to close gaps in understanding (Chaudhary 2022). This problem is exacerbated by a number of problems, including a lack of understanding of the mechanical and chemical-based characteristics of the applied nanoparticles, a lack of understanding of the mechanisms by which cells and tissues absorb nanoparticles, a lack of understanding of how nanoparticles cross the blood-brain barrier, and the ambiguous effects of various exposure routes (Gong et al. 2022).

7.6 Future Perspectives and Conclusion The understanding of neurological disease’s pathophysiology gathered over a long period of time offers the door to exciting research paths despite the lack of clarity regarding the fundamental etiology of these illnesses. Meanwhile, one of the difficulties CNS disorder treatments permeate into BBB, which substantially limits the entry of many drugs into the brain. NPs hold great promise for overcoming the barriers that the BBB erects in the way of many therapeutic and diagnostic substances’ ability to reach the CNS (Wang et al. 2020). To improve their ability to target the brain, nanocarriers like liposomes, nanoparticles, micelles, and exosomes have their surfaces altered. The BBB can be effectively crossed by nanocarriers with the aid of certain ligands (i.e., glucose, lactoferrin, transferrin, and specific peptides), enabling them to carry medications to the appropriate location that would not typically be capable to cross the BBB (Wang et al. 2017). The largest challenge among them is the low targeting efficiency, which might undermine the therapeutic benefit and harm other organs (Su et al. 2018). Another issue is the way that nanomaterials are distributed inside the brain. Sequentially targeted nanomaterials need to be taken into consideration if accurate targeting is to be accomplished in the brain. Studies on a variety of multifaceted nanomaterials that have the precisely controllable properties required for nanotherapeutics have revealed novel obstacles that must be quickly overcome. For instance, some of them have properties like less effectiveness, non-biocompatibility, and toxicity in the classifications of organisms. A few of the challenging issues being addressed include modifying and managing nanotechnology, pharmacological cargo packing, drug delivery to the brain, deep brain stimulation (DBS), implant stimulation, and brain cell activity (Kumar et al. 2021). Recently, clinical usage of nanosized biomaterials such as polymers and liposomes has been addressed. Given that the majority of the work done in the previous 10 years has been focused on proof-of-concept studies of nanoparticles for biomedical applications, nanomaterial biosafety is one of the important concerns that has to be addressed. Another significant barrier to the therapeutic application of nanodrugs is their mass manufacture. Despite these restrictions at the moment, the quick development of nanotechnologies should lead to the development of ground-breaking

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novel transportation and targeting techniques, increasing the chance that nanotechnologies will aid NDs treatment (Su et al. 2018).

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8

Nanotechnology and Nature-Sourced Ingredients for Tackling Neurodegenerative Diseases Verónica Rocha, Joana Ribeiro, Raúl Machado, and Andreia Gomes

Abstract

Neurodegenerative diseases (NDDs) pose a significant and pressing societal challenge in the twenty-first century, demanding immediate attention. Innovative approaches are actively being explored in the quest for more effective NDDs therapies. The pipeline of potential medicines offers hope, encompassing disease-­ modifying drugs, symptomatic treatments, and regenerative strategies. In parallel, natural products derived from plants are being investigated for their potential in alleviating associated symptoms but also impacting disease progression. The green synthesis of metal nanoparticles (MNPs) through environmentally friendly processes instigated the researchers to apply them in NDDs. This approach to synthesis of MNPs combines the best of both worlds, nanotechnology and natural products. Bio-inspired fabrication of MNPs proves distinct advantages over traditional methods, including scalability, low cost, and waste reduction. This chapter gives an overview of current challenges in NDDs management, current therapeutic options, and innovative strategies being developed, with a focus on nature-based solutions.

Verónica Rocha and Joana Ribeiro contributed equally. V. Rocha · J. Ribeiro Centre of Molecular and Environmental Biology (CBMA)/Aquatic Research Network (ARNET) Associate Laboratory, University of Minho, Campus of Gualtar, Braga, Portugal R. Machado · A. Gomes (*) Centre of Molecular and Environmental Biology (CBMA)/Aquatic Research Network (ARNET) Associate Laboratory, University of Minho, Campus of Gualtar, Braga, Portugal Institute of Science and Innovation for Bio-Sustainability (IB-S), University of Minho, Campus of Gualtar, Braga, Portugal e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_8

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Keywords

Neurodegenerative diseases · Natural treatments · Nanocarriers · Green synthesis of nanoparticles

8.1 Neurodegenerative Diseases as a Major Societal Challenge of This Century Neurodegenerative diseases (NDDs) comprehend an extensive variety of diseases with diverse clinical and pathological characteristics, characterized by the progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS) (Wilson et al. 2023). Loss of neural networks results in neurodegeneration implies failure in several brain functions, such as cognitive, behavior, sensory and motor (Lamptey et al. 2022; Wilson et al. 2023). Over the last three decades, there has been a significant increase in the number of fatalities and individuals experiencing disabilities as a result of neurological disorders, particularly in countries with lower- and middle-income levels (Feigin et al. 2020). Globally, in 2016, neurological disorders were the leading cause of disability-­ adjusted life-years (276 million) and the second leading cause of death (nine million). On top of that, the economic and societal ramifications of these diseases on worldwide healthcare systems are poised to escalate considerably in the forthcoming decades, driven by the progressively aging populations. Urgent measures in the search of effective therapies are thus a crucial need in upcoming years (Mortada et al. 2021).

8.2 Hallmarks of Neurodegenerative Diseases and Available Treatments NDDs share a considerable number of hallmarks (Fig. 8.1) (Choi 2021). In healthy cells, misfolded proteins are either degraded or properly refolded by chaperones (Lindberg et al. 2015). The term “proteostasis” encompasses the coordinated activity of cellular mechanisms, including the ubiquitin-proteasome system, that regulates protein production, folding, trafficking, degradation, and clearance, thereby preserving proteome functionality (Sweeney et  al. 2017; Kurtishi et  al. 2019). NDDs are associated with disruptive proteostasis, leading to an accumulation of misfolded proteins and aggregates, causing proteotoxicity, especially problematic in postmitotic neurons, and ultimately triggering stress responses in cells (Kurtishi et al. 2019). Synapses play a crucial role in the connection between neurons. Synaptic deficits, resulting from perturbations in the physiological synapse structure and function, are directly related to NDDs (Taoufik et al. 2018). Microglia, responsible for defense functions in the CNS, become activated in response to signs of injury, such as protein aggregates, misfolded proteins, damaged synapses, and reactive oxygen

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Fig. 8.1  Hallmarks of neurodegenerative diseases (NDDs)

species (ROS). Usually, this activation triggers an active resolution of the inflammatory process. However, failure to resolve it leads to chronic inflammation, potentiating neurodegeneration. Additionally, microglia interact with astrocytes, vital for maintaining a healthy brain, and their activation in the vicinity of damaged neurons results in reactive gliosis. Reactive microglia and astrocytes contribute to neuroinflammation (Wilson et al. 2023). Accumulation of ROS is another common feature of NDDs, associated with several cellular mechanisms. It leads to the deterioration of macromolecules essential for the normal cellular function (Teleanu et al. 2022). Neurons are particularly vulnerable to ROS because of the abundant presence of polyunsaturated fatty acids within their membranes. Moreover, the brain’s high oxygen consumption and antioxidant requirements, as well as its regenerative capacity, are affected by ROS accumulation, resulting in high susceptibility to oxidative damage (Bloomingdale et al. 2022). Additionally, the accumulation of DNA damage over time can ultimately lead to cellular dysfunction (Choi 2021; Wilson et al. 2023), potentially contributing to NDDs. As a result, neurons are prone to cell death, leading to brain atrophy. NDDs include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), all of which share striking similarities at the cellular and molecular level. In each one of the NDDs, there is the aggregation of a certain type of proteins associated with pathological processes: for

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Table 8.1  Misfolded proteins associated with neurodegenerative diseases (NDDs) (Parakh and Atkin 2016; Bloomingdale et al. 2022) Neurodegenerative disorders Alzheimer’s disease Parkinson’s disease Huntington’s disease Amyotrophic lateral sclerosis

Aggregating protein(s) Amyloid beta and tau protein α-synuclein Huntingtin with tandem glutamine repeats Tar DNA binding protein-43 and superoxide dismutase 1

example, β-amyloid and tau in AD, α-synuclein in PD, huntingtin in HD, and Tar DNA binding protein-43 (TDP-43) and superoxide dismutase 1 (SOD1) in ALS (Parakh and Atkin 2016; Bloomingdale et al. 2022) (Table 8.1). A commonality of all NDDs is the limited availability of effective disease-­ modifying therapeutics, primarily due to the following: (1) the complex nature and poor mechanistic understanding of the etiology of NDDs hinders the development of targeted treatments; (2) the presence of the blood-brain barrier (BBB) poses a significant challenge. It is a highly efficient physiological barrier, strictly regulating the movement of molecules between the bloodstream and the CNS (Daneman and Prat 2015; Bloomingdale et  al. 2022). Despite extensive efforts, the treatment options for several NDDs remain limited to conventional approaches. Most NDDs treatments do not modify the underlying disease process but rather focus on alleviating specific symptoms (Table 8.2). For AD treatment, five drugs are approved by the Food and Drug Administration (FDA). However, they only modestly alleviate symptoms and fall short of averting neuronal decline, brain atrophy, and, consequently, the gradual deterioration of cognitive function (Vaz and Silvestre 2020). The most recently approved drug, Lecanemab, demonstrates a modest slowing of disease progression. In the treatment of PD, only a few therapies target specific disease characteristics. Levodopa, a dopamine precursor developed in the 1960s, remains the most effective therapy to date (Stoker and Barker 2020). Management strategies for HD have had limited advances in the past 20 years, and current therapies are unable to alter disease onset or progression (Ferguson et al. 2022). Similarly, only two treatments are available for ALS, riluzole and edaravone, that slow the disease progression for a few months but cannot reverse damage to motor neurons (Jiang et al. 2022), not impacting on survival rates.

8.3 Innovative Medicines Pipeline Currently available therapies essentially rely on proteins that interact with specific target molecules to achieve a pharmacological response and control a disease (Yu et al. 2019). However, this conventional approach has inherent limitations, since (1) targets are predominantly proteins, which restricts their applicability to a limited number of diseases; (2) only a small fraction (∼1.5%) of the human genome encodes proteins; (3) epigenetic changes in a protein target can modify the response to

8  Nanotechnology and Nature-Sourced Ingredients for Tackling Neurodegenerative… 171 Table 8.2  Currently available clinical treatments of NDDs and their targets Current treatments for NDDs Alzheimer’s disease Donepezil Galantamine Rivastigmine Memantine Aducanumab

Parkinson’s disease Levodopa Bromocriptine Lisuride Pergolide Benzatropine Methixene Huntington’s disease Tetrabenazine Deutetrabenazine Olanzapine Risperidone Fluoxetine Carbamazepine

Treatment targets

References

Inhibitors of the acetylcholinesterase enzyme (AChE)

Vaz and Silvestre (2020)

N-methyl-D-aspartate (NMDA) receptor antagonist Monoclonal antibody targeting amyloid beta

Dopamine precursor Dopamine agonists ergolines

Filling the void for new Alzheimer’s disease therapy (2021) Velázquez-Paniagua et al. (2016); Stoker and Barker (2020)

Anticholinergics

Deplete central monoamines from the nerve terminal by reversibly inhibiting the human vesicular monoamine transporter 2 (VMAT2) Inhibits dopamine receptors

Reduce depression in the short term Blockade of voltage-gated sodium ion channels Amyotrophic lateral sclerosis Riluzole Anti-glutamate agent Edaravone Free radical scavenger that can reduce oxidative stress

Ferguson et al. (2022)

Jiang et al. (2022)

treatment or lead to drug resistance (Yu et al. 2019; Damase et al. 2021); (4) most protein-­based drugs are unable to freely enter target cells, thus limiting their effectiveness to extracellular or excreted target molecules (Zogg et  al. 2022); and (5) most protein inhibitors require binding to their target protein, and only a few proteins possess binding sites for small molecules (Shin et al. 2018). While these small molecules or proteins can have a significant impact in certain cases, NDDs remain without cure, and these prevailing drugs remain insufficient for effectively treating NDDS. Over the last years, researchers have dedicated substantial efforts to exploring various strategies towards identifying permanent cures. Table 8.3 outlines different types of innovative medicines currently undergoing clinical trials for each specific NDD.

Type of NDDs Alzheimer’s disease

Monoclonal antibody Synthetic small molecule Anti-tau antibody Monoclonal antibody Small-molecule oral agent Antagonist of sigma-2 receptors

Buntanetap

Zagotenemab

BAN2401

ALZ-801

CT1812

Type of therapy Agonist of sigma-1 receptor (SIGMAR1), a modulator of calcium homeostasis and mitochondrial function Anti-Aβ monoclonal immunoglobulin G4 antibody Human Aβ immunoglobulin G1 antibody

Solanezumab

Gantenerumab

Crenezumab

Agent ANAVEX2–7

Table 8.3  Agents in ongoing trials for the treatment of NDDs

Displaces Ab oligomers that are bound to neuronal receptors at the synapses

Blocks formation of oligomers

Suppresses the translation of the mRNAs of APP, tau, αSYN, and other neurotoxic aggregating proteins Selectively binds and neutralizes tau deposits in the brain Targets soluble protofibrils (large oligomers)

Binds monomeric and aggregated Aβ, with higher affinity for oligomeric Aβ Promotes clearance of amyloid plaques in the brain, through peptide aggregate dissociation and fibrillar Aβ clearance Binds to the mid-domain of soluble Aβ peptide

Mechanism of action Anti-tau, anti-­amyloid, neuroprotector, and reduces oxidative stress

Salloway et al. (2021) Fang et al. (2023) Abyadeh et al. (2021) Tolar et al. (2020) Tolar et al. (2020) Rasheed et al. (2022)

Ostrowitzki et al. (2022) Bateman et al. (2022)

References Hampel et al. (2020)

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Parkinson’s disease

Monoclonal antibody Monoclonal antibody Synthetic αSyn peptide conjugated to a T helper peptide Small-molecule glucosylceramide synthase inhibitor Cholic acid

Prasinezumab

BIIB054

UB-312

Nonabsorbable antibiotic Inhibitory chaperone Neurotrophic factor

Plasma

Rifaximin

Ambroxol

Cerebral dopamine neurotrophic factor (CDNF)

Young plasma infusions

Ursodeoxycholic acid

Venglustat

Stem cells

Mesenchymal stem cell therapy

Beneficial effects on dopamine neurons and protects neurons from endoplasmic reticulum-stress-inducing agents by modulating unfolded protein response signaling Effect unknown in PD

Prevent neuronal damage and improves PD by regulating mitochondrial function, autophagy, and apoptosis, involving AMPK/mTOR and PINK1/Parkin pathways Neuroprotective effect on the transgenic PD mice by modulating gut microbiota Reduces α-synuclein levels

Reduces glucosylceramide (GL-1) production

Induce antibodies specifically against oligomeric and fibrillar αSyn

Migrate to the site of an inflammatory response via chemotaxis and have an immunomodulatory effect on specific chemotaxis recruitment responses, thereby reducing the inflammatory response in the damaged area and promoting tissue repair Selectively binds aggregated α-synuclein at the C-terminal of the protein Targets aggregated α-synuclein

(continued)

Parker et al. (2020)

Hong et al. (2022) Mullin et al. (2020) Eesmaa et al. (2022)

Judith Peterschmitt et al. (2022) Qi et al. (2021)

Pagano et al. (2022) Kuchimanchi et al. (2020) McFarthing et al. (2020)

McFarthing et al. (2020); Zhuo et al. (2023)

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Type of NDDs Huntington’s disease

Table 8.3 (continued)

Studies suggest that it alters the levels of dopamine Stops the production of huntingtin Binds to huntingtin mRNA and decreases the production of this protein

Antibody Stem cells Chemotherapy drug Short hairpin RNA (shRNA) Antisense oligonucleotide

ANX-005

Cellavita

Nilotinib

Huntingtinlowering shRNA HTT-lowering AON

SAGE-718 Preserves synapses

Is thought to treat cognitive changes

Designed to silence the huntingtin message and inhibit the production of the mutant huntingtin Reduces the levels of huntingtin

Oral splice modulator called PTC518 NMDA receptor antagonist

AMT-130

PIVOT-HD

Studies suggest that it activates the protein sigma-1 receptor, which can have positive effects on the brain Lowers the protein huntingtin

Mechanism of action Treats involuntary movements and decreases the levels of dopamine Same mechanism of action of tetrabenazine but is broken down by the body more slowly Treats chorea

Antisense oligonucleotides (ASOs) Genetic drug

Type of therapy Vesicular monoamine transporter 2 Deuterated form of tetrabenazine Vesicular monoamine transporter

Tominersen

Pridopidine

Valbenazine

Deutetrabenazine

Agent Tetrabenazine

References De Tommaso (2011) Gupta et al. (2022) Furr Stimming et al. (2023) Asla et al. (2022) Hawellek et al. (2022) Estevez-Fraga et al. (2022) Estevez-Fraga et al. (2022) Hill et al. (2022) Lansita et al. (2017) Ferguson et al. (2022) Anderson et al. (2022) Aguiar et al. (2017) Datson et al. (2017)

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Amyotrophic lateral sclerosis

Tyrosine kinase inhibitor

Combination of sodium phenylbutyrate and tauroursodeoxycholic acid Co-inducer of heat shock proteins

Masitinib

AMX0035

Arimoclomol

Cytokine

Potent K+ channel activator

Interleukin-2

Dimethyl fumarate

Ezogabine

The combination of these two compounds act synergistically to prevent neuronal death and oxidative, bioenergetic and metabolic stress Reduced disaggregated proteins in ALS models

IL-2 is a cytokine that is important for regulatory T cell’s development and homeostasis Inhibits microglial activation

Induces membrane hyperpolarization 53 and therefore reduces neuronal excitability Increased motor neuron survival Increases regulatory T cells numbers and function

Cudkowicz et al. (2008)

Vucic et al. (2021) Giovannelli et al. (2021) Masrori and Van Damme (2020) Nikitin et al. (2023)

Wainger et al. (2021)

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8.3.1 Stem Cells Transplantation One alternative approach is stem cells (SCs) transplantation (Rahman et al. 2022). This therapy is based on the concept that transplanted cells can provide support to slow down the disease process and offer hope for restorative treatment for individuals already living with NDDS (Kiernan et al. 2021). SCs have the unique ability to differentiate into various cell types of the body while also being able to maintain a stem cell lineage (Alessandrini et al. 2019). Additionally, SCs can lead to functional improvements in nervous tissue, which could have practical clinical benefits by means of cellular substitution and immune system regulation. For example, SCs have demonstrated to influence both adaptive and innate immune responses. SCs can also migrate to sites of inflammation and exert immunomodulatory and anti-­ inflammatory effects by engaging with lymphocytes or triggering the production of cytokines (Caprnda et al. 2017). Mesenchymal stem cells, for example, secrete several neurotrophic and angiogenic factors that promote neuronal growth and differentiation, induce synaptogenesis, facilitate axonal remyelination, activate astroglial and microglial cells, and reduce apoptosis. Neural stem cells, on the other hand, are promising candidates for neural transplantation as they have the potential to differentiate into neuronal and glial lineages (Caprnda et al. 2017). SCs offer an excellent solution due to their capacity to initiate tissue regeneration, a pivotal factor in the management of neurological ailments (Namiot et al. 2022) (Fig. 8.2a).

Fig. 8.2  Examples of innovative medicines for NDDs

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8.3.2 RNA-Based Therapy RNA molecules have emerged as a new class of drugs that enable the targeting of mutated genes, which are one of the main causes of NDDS. This therapy holds the potential to expand the range of drug targets. RNA molecules such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs) and microRNAs (miRNAs) have the capability to silence target gene expression or function, thereby controlling the disease (Mollocana-Lara et al. 2021; Anthony 2022; Zogg et al. 2022). For instance, siRNA can theoretically target any mRNA that is translated into a protein, effectively silencing genes at the posttranscriptional level (Amiri et  al. 2021) (Fig. 8.2b).

8.3.3 Gene Editing Gene editing is a rapidly advancing field and the technical hurdles in harnessing genome editing as a therapy for NDDs are gradually being addressed (Kiernan et al. 2021). Clustered regularly interspaced palindromic repeat (CRISPR) exists in 90% of archaeal genomes and functions as an adaptive immune defense mechanism. The CRISPR system can capture specific gene sequences for cleavage using Cas nuclease into spacer segments derived from the exogenous genome (Fig.  8.2c). These spacers are incorporated into the CRISPR locus of host cells, transcribed into CRISPR RNA (crRNA) with spacer characteristics, and paired with foreign gene sequences in a complementary manner. Cas nuclease then destroys the target DNA, completing the immune response (Zhu et  al. 2021). An essential prerequisite for such a gene therapy approach involves the capability to precisely direct constructs to the nervous system while sidestepping any off-target effects.

8.3.4 Immunotherapy Therapies that induce adaptive immune responses, including monoclonal antibodies and specific antigen-based vaccinations, are currently under evaluation to determine their viability in the formulation of immunotherapies for NDDs (Mortada et  al. 2021). Immunotherapies provide inherent specificity, enabling the selective targeting of specific conformations. The combination of antibodies could potentially facilitate the simultaneous targeting of multiple protein aggregate species. Additionally, this type of therapy can be neuroprotective, by neutralizing extracellular protein aggregates and, consequently, reducing spread, synaptic damage, and neuroinflammation (Kwon et al. 2020). For example, immunotherapy utilizing Aβ antibodies (passive immunotherapy) or the initiation of a humoral immune response (active immunotherapy) has been the subject of extensive investigation as the primary method in Aβ-targeted therapeutic research (Fig. 8.2d) (Winblad et al. 2014).

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8.3.5 Natural Products for Disease and/or Symptoms Management For centuries, natural products and their bioactive compounds have been employed for medicinal purposes (Chaudhary et al. 2023). In recent years, natural products have been extensively investigated. Numerous studies have demonstrated the protective effects against various diseases, including NDDs, for which current therapies are often inadequate and primarily focused on alleviating symptoms (Rahman et  al. 2021). While each specific disease has its unique pathogenic mechanisms, neurodegeneration, encompasses a sequence of events that culminate in the gradual deterioration of neurons’ functional characteristics, ultimately resulting in cell death, a pivotal aspect of NDDs (Chaudhary et al. 2022). However, there are common hallmarks in these diseases, where the same compounds can be implemented, such as preventing protein misfolding, antioxidant activity, reducing neuroinflammation, antiapoptotic and acetylcholinesterase activity (Sharifi-Rad et  al. 2020). The application of natural products has gained momentum due to dissatisfaction and shortcomings of traditional drugs, issues related with their increasing cost and availability worldwide, as well as advancements in the quality and safety of herbal compounds facilitated by technological developments (Di Paolo et  al. 2019). Table 8.4 presents various plant species and natural compounds that can be utilized in NDDs treatment. Table 8.4  Different types of plant species or natural compounds along with their biological effects Plant species or natural compound Ginkgo biloba Panax ginseng C.A.

Scutellaria baicalensis Georgi Curcuma longa Vitis vinifera Salvia officinalis L. Caffeine Bacopa monniera

Centella asiatica Picrorhiza scrophulariiflora Apium graveolens L.

Oxalis corniculata

Biological effect Boosts circulation to the brain Neurons survive longer by increasing their supply of survival compounds known as neurotrophic factors Protect neurons from oxidative damage Inhibition of cytokine production and microglia activation Neuroprotective effects Anticholinesterase activity Acts on adenosine receptors Enhancing neuronal synthesis, kinase activity, restoring synaptic activity, and nerve impulse transmission Antioxidant action Neuritogenic activity

References Mashayekh et al. (2011) Miranda et al. (2019)

Attenuated oxidative stress, decreased monoamine oxidase activity, and protected dopaminergic neurons Improved memory retention and retrieval

Chonpathompikunlert et al. (2018)

Yoon et al. (2017) Yu et al. (2002) Tabeshpour et al. (2018) Kennedy et al. (2006) López-Cruz et al. (2018) Mathur et al. (2016)

Hafiz et al. (2020) Kumar et al. (2008)

Aruna et al. (2017)

8  Nanotechnology and Nature-Sourced Ingredients for Tackling Neurodegenerative… 179 Table 8.4 (continued) Plant species or natural compound Nigella sativa

White rose petal extract

Phragmanthera austroarabica Tabernaemontana divaricata Huperzine A

Quercetin Baicalein Wogonin

Rutin Smallanthus sonchifolius Natural safflower aqueous extract Methanolic extract of Lactuca capensis Thunb. leaves Turmeric powder Germinated brown rice Withania somnifera

Turbinaria ornata Carotenoids

Biological effect Enhanced remyelination in the cerebellum and suppressed inflammation Inhibited lipid peroxidation, downregulated mRNA expressions of antioxidant enzymes, and downregulated mRNA and protein expressions of inflammatory mediators Increased the percentage of viable neurons Prevented memory loss, decreased lipid peroxidation, and increased neuronal density in the hippocampus Natural, potent, highly specific reversible inhibitor of acetylcholinesterase Promotes the reduction in oxidative stress and increased cognition Antioxidant and anti-inflammatory effects Various neuroprotective and neurotrophic activities, such as inducing neurite outgrowth Antioxidant and anti-inflammatory Memory deficits prevented Short- and long-term memory improved Lowering the degree of lipid peroxidation and protein oxidation Improvement in the quality of life and behavioral symptoms Reduced production of intracellular ROS Significantly improved executive functions in adults with mild cognitive impairment Antioxidant, anti-inflammatory, and neuroprotective effects Antioxidant, anti-inflammatory, and autophagy-modulatory activities

References Noor et al. (2015)

Yon et al. (2018)

Aldawsari et al. (2017) Khongsombat et al. (2018)

Villegas et al. (2022)

Mani et al. (2018) Shi et al. (2021) Huang et al. (2017)

Xu et al. (2014) Martinez-Oliveira et al. (2018) Zhang et al. (2019) Ionita et al. (2018)

Hishikawa et al. (2012) Azmi et al. (2015) Gopukumar et al. (2021)

Remya et al. (2022) Cho et al. (2018)

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8.4 Intervention of Nanotechnology for Improved Therapeutic Potential Nanotechnology impact in biomedicine offers several applications including diagnostics, imaging and contrast agents, drug delivery systems, and antimicrobial materials (Tripathi and Chung 2019; Sim and Wong Kui 2021). It has been applied extensively in drug delivery to improve the therapeutic outcomes of neurological diseases, shielding lipophilic compounds, facilitating extended release, and enhancing drug absorption (Patra et al. 2018). Specifically, therapeutic strategies for NDDS involving nanotechnology must always be mindful of the complexity of CNS, particularly the BBB, which restricts the influx of biomacromolecules and drugs delivered through oral and intravenous routes (Masoudi Asil et al. 2020). Nanoparticles can be designed to maximize BBB penetration (through adsorptive and receptor/ transporter-mediated transcytosis) and, ideally, either respond to specific triggers and/or target specific molecules (intra- or extracellular) for enhanced selectivity. Furthermore, the BBB possesses efflux systems, which usually serve for protection against hazardous exposure to chemicals, for example, that may also limit the permanence of the nanoparticles within the CNS and this of their therapeutic efficiency. Research has shown demonstrated that natural compounds have possess potential anti-inflammatory, antioxidant, and immunomodulatory properties, making them therapeutically valuable, which are of significant therapeutic value in a wide range of for various (Khadka et al. 2020) (Table 8.4). However, numerous natural compounds demonstrate diminished solubility, stability, bioavailability, and target specificity, rendering direct clinical implementation unfeasible (Khadka et al. 2020; Bakrim et al. 2022). Nanotechnology offers the opportunity to overcome these limitations. Several studies have combined the use of nanomaterials with commercially available bioactive compounds, such as curcumin (Brahmkhatri et  al. 2018; Fan et al. 2018), resveratrol (Yang et al. 2018; Abozaid et al. 2022), epigallocatechin-­3-­ gallate (Cano et al. 2019, 2021), quercetin (Liu et al. 2019; Rifaai et al. 2020), naringenin (Md et al. 2018; Dashputre et al. 2023), ferulic acid (Shukla et al. 2022; Garcia et al. 2023), caffeic acid (Andrade et al. 2023), and rosmanic acid (Chung et al. 2020), showing great potential as therapeutic agents for NDDs. In recent years, researchers have focused explored on various natural compounds extracted from sea organisms, including marine macroalgae, which that exhibits numerous various biological activities, including neuroprotection (Hannan et al. 2020; Menaa et al. 2021; Remya et al. 2022). For instance, fucoxanthin, a marine carotenoid derived from edible brown algae, has shown neuroprotective properties by preventing Aβ aggregation, inhibiting oxidative stress, and reducing neuroinflammation (Cho et  al. 2018). However, its low water solubility and poor BBB penetration limit its clinical application. Yang et al. (2021) extracted fucoxanthin from Sargassum horneri and synthesized fucoxanthin-loaded poly lactic-co-glycolic acid-block-polyethylene glycol nanoparticles (PLGA-PEG-Fuc NPs) that allowed the controlled release of fucoxanthin in a physiological environment, with significant inhibition of the formation of Aβ fibrils and oligomers. The application of natural compounds in the synthesis of nanoparticles presents challenges which must be considered.

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Importantly, the type of plant extract used is known to influence the characteristics of the metal nanoparticles (MNPs) produced, since different plant extracts contain different concentrations of organic reducing agents, which implies a previous optimization of the synthesis process (Rahimi-Nasrabadi et al. 2014). Also, the stability of MNPs differs according to the biological entities used (Salem and Fouda 2021).

8.5 Green Synthesis of Metal Nanoparticles Combines the Best of Both Worlds Current pharmacology faces a significant obstacle in creating neuroprotective medications using environmentally friendly and safe methodologies (Pathania et  al. 2022). Within the extensive spectrum of nanostructured materials, MNPs are regarded as fundamental building blocks of nanotechnology, serving as a link between bulk materials and atomic or molecular structures (Sharma et al. 2019; SI et al. 2020). MNPs have an extensive range of biomedical applications, including drug delivery, diagnostics, bioimaging, catalysis, photoablation therapy, and biosensors (Gautam et al. 2022). However, conventional techniques for synthesizing MNPs are constrained by factors like high energy demands, the need for specific and expensive equipment, generation of combustible hydrogen gas, and the employment of hazardous chemicals, such as sodium borohydride, cetyltrimethylammonium bromide, or sodium citrate, which are hazardous to the environment and biological systems (Saravanan et al. 2021). An alternative approach utilizing prokaryotic/eukaryotic cells or extracted biomolecules as reducing, stabilizing, and capping agents has gained great attention (Rana et al. 2020). These green synthesis processes involve microorganisms (bacteria, fungi, yeasts), algae, and plant biomass or extracts (Gupta et al. 2023; Tauseef et al. 2023; Thukral et al. 2023). Bio-­ inspired fabrication of MNPs proves economical, straightforward to execute, diminishes chemical impact on the environment, obviates superfluous steps in synthesis, and is generally regarded as safe for different routes of administration (Marslin et al. 2018; Khan et al. 2019). Recent developments in the application of green MNPs support great potential in biomedicine (Guleria et al. 2022; Nieto-Maldonado et al. 2022; Chandrababu et al. 2023). However, knowledge regarding their potential in neurodegeneration is still limited. Table 8.5 summarizes reports highlighting the therapeutic potential of biosynthesized MNPs in NDDs. The very first report on biosynthesized MNPs and their application for NDDs describes the antioxidant activity of gold nanoparticles (Au-NPs) produced in Curcuma longa root extract against 1-methyl-2-phenyl pyridinium ion (MPP+)induced cytotoxicity in PC-12 cells (Nellore et al. 2012). Since then, an increasing number of publications have provided further evidence supporting the potential of green MNPs as therapeutic agents for NDDs. Biosynthesized Au-NPs have gathered significant attention due to their stability, non-toxicity, resistance to oxidation, and biodegradability, stemming from their small size, shape, dose, and atomic configurations. Sattarahmady et al. (2018) compared the impact on amyloid fibrils in PC12

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Table 8.5  Biosynthesized metal nanoparticles (MNPs) as a therapeutic agent in the treatment of neurodegenerative disorders (NDDs) Green MNPs Ag

Extract Pulicaria undulata L.

Lampranthus coccineus and Malephora lutea Nepenthes khasiana Aquilegia pubiflora Rosa Galaxaura elongata, Turbinaria ornata, and Enteromorpha flexuosa Hypecoum pendulum Au

Citrus aurantium L. and Rose damascena Terminalia arjuna

Ephedra sinica Stapf

Olax scandens Cinnamomum verum

Crocin from Crocus Sativus L. Heliotropium eichwaldi L Hibiscus sabdariffa

Ag/Au

Hippeastrum hybridum

Therapeutic effects Preventing the aggregation of α-lactalbumin and no effect on the chaperone ability of α-casein Anticholinesterase and antioxidant activity

References Dehvari and Ghahghaei (2018) Youssif et al. (2019)

Prevention of the effect of deficits in recognition and spatial memory Inhibition of anticholinesterase Inhibitory effects on protein aggregation Inhibition of anticholinesterase

Zhang et al. (2020) Jan et al. (2021a) Rauf et al. (2022) Azeem et al. (2022)

Inhibition of anticholinesterase

Huda et al. (2023) Sattarahmady et al. (2018) Suganthy et al. (2018)

Inhibition of amyloid fibril formation Inhibition of acetylcholinesterase and butyrylcholinesterase; suppression of the fibrillation of Aβ and destabilization of the preformed mature fibrils. Pro-inflammatory mediators and cytokines were downregulated; suppressing activation of a variety of neuroinflammation signaling pathways. Chaperone potential against protein aggregation Reduction effect of MPTP-induced oxidative stress and motor abnormalities; Attenuation of Tumor Necrosis Factor-α, Interleukin-1β and Interleukin-6 expression levels Inhibition of aggregation of α-lactalbumin Inhibition of anticholinesterase Inhibition of aggregation of α-lactalbumin Inhibition of anti-acetylcholinesterase

Park et al. (2019)

Mujeeb et al. (2019) Ling et al. (2019)

Nouri et al. (2021) Sher et al. (2023a) Talebpour and Ghahghaei (2020) Sher et al. (2023b)

8  Nanotechnology and Nature-Sourced Ingredients for Tackling Neurodegenerative… 183 Table 8.5 (continued) Green MNPs ZnO

Extract Aquilegia pubiflora

Moringa oleifera

Pt

Bacopa monnieri

Therapeutic effects Inhibiting the enzymes butyrylcholinesterase and acetylcholinesterase Reduced acrylamide-induced sensory dysfunctions, hind limb abnormality, and motor deficits; Inhibition of anti-acetylcholinesterase Alleviating the ROS generation and scavenging free radicals

References Jan et al. (2021b)

Dahran et al. (2023)

Nellore et al. (2013)

MPTP 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine

cells exposed to Au-NPs either chemically synthesized with sodium citrate or biogenically produced using oil extracts of Citrus aurantium L. blossoms and Rosa damascena as reducing and stabilizing agents. The results demonstrated that the biogenic Au-NPs were more effective in inhibiting fibril formation than the chemically synthesized Au-NPs. Other studies have revealed the potential of green Au-NPs in inhibiting the aggregation of α-lactalbumin (Talebpour and Ghahghaei 2020; Nouri et al. 2021). Green Au-NPs also efficiently suppressed the fibrillation of Aβ and destabilized the preformed mature fibrils (Suganthy et  al. 2018). Park et al. (Park et al. 2019) investigated the anti-neuroinflammatory of Au-NPs synthesized with Ephedra sinica Stapf in microglia, providing new insights into the role of green Au-NPs in treating chronic neuroinflammation-induced NDDs. Interestingly, Sher et  al. (2023b) developed an eco-friendly protocol to synthesize Ag/Au NPs using Hippeastrum hybridum extract for targeting acetylcholinesterase in rat brains. Silver nanoparticles (Ag-NPs) also exhibit distinctive attributes, including high electrical conductivity, chemical stability, catalytic activity, and antimicrobial capabilities (Dehvari and Ghahghaei 2018). Youssif et  al. (2019) demonstrated that Ag-NPs synthesized with aqueous extracts of Lampranthus coccineus and Malephora lutea were able to cross the BBB in vivo, modulate acetylcholinesterase activity, and reduce harmful oxidative stress levels. Other reports revealed the inhibitory potential on acetylcholinesterase of Ag-NPs synthesized with Aquilegia pubiflora (Jan et  al. 2021a), Hypecoum pendulum (Huda et  al. 2023), Galaxaura elongata, Turbinaria ornata, and Enteromorpha flexuosa (Azeem et  al. 2022). Dehvari and Ghahghaei (Dehvari and Ghahghaei 2018) demonstrated that Ag-NPs from Pulicaria undulata L. prevented the aggregation of α- lactalbumin without affecting α-casein’s chaperone activity. Ag-NPs synthesized from rose petals exhibited inhibitory effects on protein aggregation (Rauf et  al. 2022). Furthermore, another study reported that Ag-NPs biosynthesized in Nepenthes khasiana prevented deficits in recognition and spatial memory in streptozotocin-induced diabetes (Zhang et al. 2020). Although the majority of the most literature is focused on the biosynthesis of Au- and Ag-NPs, a few studies with green zinc oxide nanoparticles ZnO NPs (Jan et al. 2021b; Dahran et al. 2023) and platinum (Pt-NPs) (Nellore et al. 2013) are also available.

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8.6 Conclusion Neurological disorders are the leading cause of disability-adjusted life-years and the second leading cause of mortality. In recent years, researchers have dedicated substantial efforts to exploring various strategies for identifying permanent cures. Natural products have been extensively investigated; nevertheless, their direct clinical application is very often unfeasible and nanotechnology may resolve most of their limitations. The development of neuroprotective drugs through eco-friendly and safe processes is a major challenge in current pharmacology. Green MNPs are an alternative approach. The majority of the available literature is focused on the biosynthesis of Au- and Ag-NPs and different therapeutic effects are studied, such as preventing the aggregation of α-lactalbumin, inhibition of the enzymes acetylcholinesterase and butyrylcholinesterase, prevention of the effect of deficits in recognition and spatial memory, and inhibition of amyloid fibril formation. However, our comprehension of their possible role in neurodegeneration is currently restricted. In order to enhance treatment options for NDDs, more research is required to gain a better understanding  of the pathology and how new strategies can disrupt the underlying processes.

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Deciphering the Role of Nanomedicines for the Treatment of Ischemic Stroke Faizan Ahmad, Anik Karan, Navatha Shree Sharma, Vaishnavi Sundar, Richard Jayaraj, and Umme Abiha

Abstract

Ischemic stroke (IS) affects 15 million people globally which leads to death or disability. Currently, Tissue plasminogen activator (tPA) is the only medication approved by the US Food and Drug Administration (FDA) for treating IS. This treatment eliminates the brain’s blood shortage and the reperfusion-related adverse effects that cause significant tissue damage. Therefore, novel treatment approaches are urgently needed to preserve the integrity of the blood-brain barrier (BBB) and salvageable brain tissue. Nanomedicine opens a new door for emerging strategies that can be promising therapeutic approaches for IS.  This chapter first discusses the pathophysiology and different events of IS, then availF. Ahmad Department of Medical Elementology and Toxicology, Jamia Hamdard University, Delhi, India A. Karan (*) CL Lab LLC, Gaithersburg, MD, USA N. S. Sharma Department of Surgery Transplant and Mary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Centre, Omaha, NE, USA V. Sundar Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA R. Jayaraj Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE U. Abiha IDRP, Indian Institute of Technology, Jodhpur, Rajasthan, India All India Institute of Medical Sciences, Jodhpur, Rajasthan, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_9

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able therapeutic interventions for IS followed by different nanocarriers available. This chapter also covers viral vectors and extracellular vesicles for IS. Also, it focuses on the intranasal administration of nanomedicines, which might cross the BBB and finally discusses toxicity related to nanocarriers for IS. This chapter is completely focused on using nanomedicines for the use of IS. Keywords

Ischemic stroke · Blood-brain barrier · Nanomedicine · Therapeutics · Nanocarriers

9.1 Introduction Stroke is the most common cerebrovascular disease, which can cause both psychological and physical impairments. Stroke affects 15 million people annually, and it is estimated that by 2030, around 23 million cases will be reported, including 7.8 million deaths (Yang et al. 2018; Zhu et al. 2018; Hsieh et al. 2010). Stroke is considered one of the 19 deaths, with a mortality rate of around 30% in the United States of America. Numbness, confusion, and aphasia are the most common symptoms of a stroke. Stroke is mainly divided into three categories: ischemic stroke (IS), haemorrhagic stroke, and transient ischemic attack (TIA). IS happens due to disruption of blood flow, which is seen in 80–90% of cases. Haemorrhagic stroke occurs when blood vessels burst, leading to severe blood leakage, and in TIA, blood flow blocks for a short period. TIA damage is comparatively less than the other two conditions (Shichita 2018; Lai et al. 2014; Rodrigo et al. 2013). For the management of IS, tissue plasminogen activator (tPA) is the only approved treatment available in the market (Rother et al. 2013). tPA is administered intravenously within 3–4.5 h of the stroke attack. Endovascular thrombectomy is the standard treatment for a patient with large vessel occlusion. Currently, researchers are trying to understand cellular and molecular mechanisms that can lead to developing promising therapies that can reduce brain damage from ischemic abrading (Powers et al. 2015; Campbell et al. 2019; Indo et al. 2015). When cerebral ischemia occurs, complicated pathogenic processes are set off, discussed in detail. First, the halting of cerebral blood flow (CBF) leads to an oxygen and glucose shortage. It leads to a reduction in ATP level. It promotes rapid calcium influx, which triggers multiple key pathological events of IS like inflammation, apoptosis, elevated reactive oxygen species (ROS), and mitochondrial dysfunction (Yamada et al. 2020), which can lead to irreparable tissue damage and infraction. ROS are mainly generated by oxidative phosphorylation, which regulates multiple signalling pathways that regulate various cellular activities (Luo et al. 2019a, b). An antioxidant defence mechanism is made up of numerous antioxidants like coenzyme Q10, glutathione, etc., which actively control ROS as well as keep it at a healthy level for good cell upkeep. This defence mechanism’s ineffective operation causes oxidative stress, which in turn causes mitochondrial dysfunction (Sims and Muyderman 2010). Therefore, thorough

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research is needed to create an effective pharmaceutical molecule or compound combating cerebral ischemia, and knowledge of pathogenic changes in neuro microvasculature is necessary. As a result, neurotherapeutics that reduce ROS generation and manage mitochondrial oxidative stress may be effective treatments for IS. It is impossible for all medicines to cross the blood-brain barrier (BBB) (Lin et al. 2016). Thus, novel approaches with improved efficacy, delivery efficiency, and minimal side effects are needed. Nanoscience has recently attracted much attention, since it offers safe and efficient drug delivery methods (DDMs) that can cross BBB. This is because they are more stable and have active/passive directing properties, which can enhance medication concentration at the lesion site to provide desired therapeutic reverberations (Lin et al. 2016). Thorough cognizance is necessary to develop and use various nanotherapeutic approaches. As a result, we extensively discussed the pathological processes resulting from ischemia injury in this chapter, emphasizing mitochondrial damage with the current therapeutic options and their drawbacks. Most importantly, this chapter summarizes IS management from nanoparticles. We also tried to cover DDSs, including their nanocarriers that are a part of them, which might serve as guidance and valuable knowledge regarding NPs usage in translational research and carrying drugs from lab to bedside.

9.2 Understanding Pathophysiological Events of IS When CBF drops to 20 mL/100 g tissue/min from the average 50–60 mL/100 g tissue/min, it leads to electrical silencing and impaired neuronal functioning. A further drop in CBF may cause irreversible neuronal cell death due to metabolic impairment. Moreover, decreased blood flow may lead to lower levels of glucose, oxygen, and several critical components, which leads to acidosis. Mitochondrial dysfunction, inflammation, oxidative stress, apoptosis, and excitotoxicity ultimately emerge as crucial factors in the overall development of IS (O’Donnell and Yuan 2019; Sommer 2017) (Fig. 9.1).

9.2.1 Excitotoxicity in IS Excitotoxicity is another central underlying process causing ischemia damage. Excessive excitatory amino acid production and reduced excitatory amino acid reuptake are brought on by energy loss. Metabotropic glutamate receptors like AMPA and NMDA get activated by elevated glutamate levels in synapses, triggering some disturbance in calcium homeostasis. Excitotoxic glutamate stimulation leads to calcium influx, which later on causes intracellular calcium overload. This leads to apoptosis and inflammation, which set off a detrimental chain of metabolic events (Chamorro et  al. 2016; Gascon et  al. 2008; Besancon et  al. 2008; Bao et al. 2018).

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Fig. 9.1  Blocked blood vessels in ischemic stroke observed, and different pathophysiological events like excitotoxicity in which excessive glutamate release with neuroinflammation bloodbrain barrier (BBB) breakdown and ROS production

9.2.2 Nitrative and Oxidative Stress in IS Oxidative and nitrosative stress-induced injury can result from the antioxidant defence system’s inability to effectively scavenge free radicals, which can be brought on by high oxygen consumption and high levels of oxidized lipids with low endogenous antioxidant capacity (Bao et al. 2018). Free radical production had also been found to rise after the stroke and, therefore, likely to contribute to stroke damage. During IS, ROS and nitrogen species (RNS) also play a vital role in mediating tissue damage (Tian et al. 2020; Ballarin and Tymianski 2018). Peroxynitrite is a potent oxidant that may be created when superoxide and the NO molecule, as it gets generated through NOS and stimulated through ischemia, interact. RNS might exert substantial biological consequences, like DNA damage and mitochondrial enzyme inhibition. Moreover, biological consequences increase the overall intake of Ca2+ ions by stimulating the Ca2+ permeable cation channel subfamily M member seven channels. Furthermore, NO might impact cells by regulating crucial proteins like metalloproteases, caspases, and glycolytic enzymes (Khoshnam et al. 2017; Pradeep et al. 2012).

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9.2.3 Neuroinflammation in IS During cerebral ischemia, various chemicals, including cytokine and lymphokines secreted by damaged tissues and ROS species, trigger and mediate inflammatory cascade. Ischemia also promotes the conversion of microglial to phagocytic cells (Zhao et al. 2017). Stimulated microglial produce interleukin-1 (IL-1), interleukin-6 (IL-6), etc. in response to ischemia (Guruswamy and El Ali 2017). Though stimulated microglial primarily maintains neuronal cells, excessive microglial activation culminates in severe inflammation, including neuronal death. Toll-like receptors (TLRs) are mainly found within neurons, astrocytes, endothelial cells, as well as the microglia of the human brain. TLR4 increases on the microglial surface if the oxygen level is low (Sun et al. 2015). TLRs may trigger transcription factors that lead to the nucleus gene expression of cytokines, integrin molecules, or proinflammatory substances. After ischemia, endogenous ligands like Hsp70 become elevated, which might activate TLRs to contribute to ischemic damage (Yao et al. 2017).

9.3 Established Treatment Strategies for IS Currently, thrombolysis, endovascular thrombectomy, anticoagulant, anti-platelet therapy, and neuroprotective therapy are available as treatment options for IS.  Thrombolysis and endovascular thrombectomy focus on reducing blot clots, whereas all other treatments concentrate on reducing neuronal cell ischemia damage. In addition to these tactics, nursing care for IS patients after therapy is essential (Shekhar et al. 2018; Hill and Towfighi 2017).

9.3.1 Thrombolytic Therapy for IS According to pharmacological theory, plasminogen starts a fibrinolytic cycle that breaks down in the presence of a plasminogen activator and produces plasmin and transformation from solid fibrin to liquid products by plasmin (Seners et al. 2016; Leiva-Salinas et al. 2016). Many consequences, including cardiac arrest or cerebral stroke, can develop whenever there is any imbalance between coagulation and fibrinolysis (Prabhakaran et al. 2015; Majidi et al. 2018). Recombinant tPA (rt-PA or alteplase) is administered intravenously and is the sole therapy for IS approved by the US FDA. A mediator that stimulates fibrin-bound plasminogen is tPA. Clinical studies on alteplase have produced positive results (Majidi et al. 2018). Nevertheless, neither the Alteplase Thrombolytic for Acute Noninterventional Treatment in Ischemic Stroke (ATLANTIS-B) trials nor any European Cooperative Acute Stroke Study II (ECASS II) demonstrated their anticipated results. Yet, they were integrated into a meta-analysis comprising more than 2000 patients who received treatment around 6 h after their stroke began. After 4.5 h, alteplase had no impact. The ECASS III study confirmed alteplase’s persistent benefit in 3–4.5 h; delays beyond this point raised the risk of thrombolytic-mediated asymptomatic intracerebral

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haemorrhage. Several additional thrombolytic drugs have been developed recently, including under either fibrin-specific or nonspecific categories, which do not distinguish between fibrin-bound and free plasminogen (Ueno et al. 2018; Saver et al. 2016; Matsumoto et al. 2018; Luo et al. 2019a, b).

9.3.2 Mechanical Thrombectomy for IS Endovascular mechanical thrombectomy (EMT) is one alternative method of clot removal for those not candidates for thrombolysis or alteplase IV (Bansal et  al. 2013). Furthermore, in 2015, several randomized multicentre trials suggested mechanical thrombectomy preferable to intravenous rt-PA for treating cerebral artery blockage. Hence, EMT and rt-PA may be therapy guidelines prescribed in IS without significant artery obstruction (Fischer et  al. 2017; Friedrich et  al. 2016). While the therapy has actual worth, limited people benefit because it is relatively less common or intervention gets delayed. Hence, EMT and rt-PA may be a therapy the guidelines prescribe for IS with significant artery obstruction. Although this treatment has absolute worth, few patients benefit from it because it is less prevalent or because treatment is delayed (Powers et al. 2018, 2019).

9.3.3 Photothermal Therapy (PTT) for IS Cancer patients have frequently received photothermal therapy (PTT). To accomplish tumour ablation in PTT, there should be a rise in the temperature of photothermal agents (Tan et al. 2018). With benefits like significant therapeutic efficacy and minimum invasiveness, graphene and black phosphorus are also used in phototherapy for neurological illnesses. Moreover, with NIR irradiation, black phosphorus nanosheets could obtain increased BBB permeability (Xie et al. 2018; Liang et al. 2019). Other therapeutic advantages of black phosphorus include reduced ROS production with high mitochondrial membrane potential (MMP). Lasers can induce smart medication release in conjunction with the apparent cytotoxic effects of photothermal therapy (Kim et al. 2016; Liu et al. 2017a, b; Li et al. 2018). Qiu et al. created a biodegradable black phosphorus hydrogel for an intelligent drug delivery platform, in which black phosphorus nanosheets and agarose aqueous solution combined together following the medication was loaded by electrostatic adsorption to create black phosphorus hydrogel. This hydrogel has the potential to undergo reversible hydrolysis and soften in response to a laser-induced rise in temperature, enabling photo-controlled drug release, and in the dark state, the drug release rate of the black phosphorus hydrogel is dramatically increased by irradiation. Clinical use of light-controlled medication release for stroke treatment is possible (Qiu et al. 2018).

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9.3.4 Neuroprotective Therapy for IS I/R injury currently has primarily palliative therapy options, which infrequently address the condition’s underlying causes. Hence, novel therapeutics are needed to counteract neuronal degeneration (Matsumoto et al. 2018). A novel treatment strategy termed neuroprotection entails the neurological restoration or regeneration of the operational results in increasing neuron survival after IS and lengthen its therapy window. Nevertheless, no viable treatment may stop IS-related neural tissue destruction. These pathogenic phenomena connected to IS are mainly controlled by neuroprotective therapy (Luo et al. 2019a, b; George and Steinberg 2015; Boltze et al. 2012). Because it produces ROS and pro-inflammatory cytokines, which target neuroinflammation, it is widely recognized for its detrimental effects, which encourage permanent cell death. According to numerous studies, mitochondrial dysfunction has a significant role in IS. As already mentioned, ROS causes mitochondrial dysfunction, which is crucial to the pathophysiology of IS. Approaches directly targeting mitochondria and enhancing mitochondrial bioenergetics will boost exceptional therapeutic ability in these circumstances, exhibiting an inherent antioxidant power (Poupot et  al. 2018; Mondal et  al. 2019). The neuroprotective pharmacological drugs that scavenge ROS may prevent ischemic neurons from irrevocable harm by primarily focusing on mitochondrial malfunction. Neuroprotective drugs like GABA agonists, NO antagonists, calcium channel blockers, and calcium chelators can be classified based on functional activity (Chen et al. 2020; Kikuchi et al. 2012; Inzitari and Poggesi 2005; Yi et al. 2020).

9.3.5 Role of Anticoagulant and Anti-platelet Therapy for IS Anticoagulant and anti-platelet medication can be used to manage IS in surgical as well as nonsurgical procedures (Volpe et al. 2017). Aspirin is also used as an antiplatelet medication by a large number of people as it minimizes clot development by inhibiting platelet adhesion, thus avoiding repeated thrombolysis. Information suggests dual therapy, which combines anti-platelet drugs with clot dissolution, has improved outcomes than monotherapy (Testa et al. 2019; Powell 2015). Nevertheless, bleeding is one of the side effects of dual therapy. Anticoagulants cause symptomatic cerebral bleeding when administered to patients who weren’t adequately chosen, which negates the intended benefit. Heparin, rivaroxaban, danaparoid, warfarin, apixaban, and dabigatran are the most frequently prescribed anticoagulants (Peng et al. 2017; Dmytriw et al. 2020).

9.4 Changing BBB Permeability in IS After brain ischemia, tight junction protein clustering at the BBB is altered by oxidative stress brought on by ROS generation, which increases paracellular leakage. Astrocytes even play a vital role in the BBB disintegration after ischemia injury. IS

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causes the BBB to open from minutes to hours. Reperfusion of the ischemic zone and restoring blood flow is long-term opening from hours to days. Proteins and red blood cells are prohibited items that might enter the injured brain parenchyma due to BBB failure (primary and secondary opening). Due to good fluidity and narrowness, nanomedicines have prospects in the leaky BBB (Takemori et al. 2013; Shindo et al. 2016).

9.4.1 Active BBB Transport Mechanisms in IS Transcytosis is another intriguing method for encouraging the passage of nanomedicines via the BBB.  Active transport, including adsorptive and receptor-­ mediated transcytosis, has been studied to establish intercellular spacing and enhance selective targeting. The negatively charged BBB luminal surface interacts with positively charged nanoparticles, causing endothelial membrane adsorption and possible transcytosis. Another intriguing strategy to boost BBB transport involves cell-penetrating peptides and cationic proteins. Receptor-mediated transcytosis is an alternate method for crossing the BBB in the early hours following damage (Meloni et al. 2014, 2015; Bhaskar et al. 2010).

9.5 Role of Nanocarriers in the Drug Delivery System in IS Drug delivery system has the potential to permit the targeted as well as controlled release delivery of medicinal substances in a variety of neurological conditions (Chaudhary et al. 2023). DDSs have significantly benefited from nanocarriers’ ability to enhance the penetration of medicines across BBB (Fig.  9.2). Research is mainly focused on polymeric nanoparticles (NPs), which are made of polylactic acid (PLA), poly (D.L.-lactide-co-glycolide) (PLGA), and polyglycolic acid, which can be promising drug-targeted delivery. Polymeric NPs are coated with chitosan, lectin, and D-tocopherol polyethylene glycol 1000 succinate (TPGS), which can help increase the stealth and effectiveness of NPs. Solid lipid NPs are a different strategy for effective brain targeting than polymeric NPs (Patra et  al. 2018; Suk et al. 2016).

9.5.1 Features of Nanocarriers The overall objective of medication delivery using nanocarriers is to cure diseases with the fewest side effects. High lipophilicity and small-sized molecules are favourable for passive diffusion across the BBB. A compound’s permeability and solubility are believed to be related to lipophilicity. Nevertheless, lipophilicity has two disadvantages. High lipophilicity may cause the medicine to metabolize, be poorly soluble, and absorb quickly. Hence, using DDSs based on nanotechnology for controlling and targeted release of such compounds may be an appropriate

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Fig. 9.2  Different nanocarriers targeting blocked blood vessels of ischemic stroke

strategy (Saeedi et al. 2019). Size, form, rigidity, hydrophobicity, as well as different elemental compositions are important factors that must be considered while creating synthetic nanostructures, which is important for the use of nanomaterials in day-to-day life activities (Masoudi Asil et al. 2020). NPs can be artificial or natural, with sizes of 1–1000 nm. NPs include liposomes, gold NPs, nanotubular particles, inelastic spherical shells, micelles, and polymers. Increased lipophilicity, polarity determination, or adding surface receptors that can recognize a particular cell type may help to improve the NP as a potential drug delivery component. Formulation’s therapeutic efficacy is enhanced by the thickness and size of the NP capsules, which can range from 1 to 300 nm. The percentage from a core over the surface depends on the NP’s size. The quick release of the drug upon penetrating the NP’s membrane is made possible by the smaller NP’s reduced core-to-surface ratio. Larger NPs are not ideal because they have drawbacks, including slow disintegration or drug trapping in the carrier, which results in unequal or ineffective drug administration (Neetika et al. 2023). Another crucial aspect of medicine is its timing of release. The adaptability of NPs to fuse or adapt with different biological components, such as antibodies and peptides, can increase their suitability as medication carriers (Panagiotou and Saha 2015).

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9.5.2 Types of Nanocarriers for IS Organic and inorganic nanocarriers are the two primary categories of modern smart nanostructured systems and biological vectors, which can be the third type of nanocarriers (Domenico et al. 2019).

9.5.2.1 Organic Nanocarriers for IS Organic nanocarriers have a relatively high medication-carrying capacity and are biocompatible. 9.5.2.1.1  Polymeric Nanocarriers for IS Due to their excellent sustained-release characteristics and outstanding biocompatibility, polymeric nanoparticles have been investigated as promising drug delivery platforms (Wang et al. 2015; Zuckerman et al. 2014; Beyth et al. 2010). Polymeric nanoparticles have drawbacks, such as high cost and complex manufacture. Based on a recent study, a hydrophilic dye called fluorescein isothiocyanate (FITC) was used to encapsulate PLGA nanoparticles in balloon-expandable stents (Mdzinarishvili et al. 2013). Recently, cationic polymer micelles with the ability to identify brain stem cells were developed. Using magnetic resonance imaging (MRI), it has been indicated that the micelles are highly effective, safe, and reliable for tracking stem cells in vivo (Mouheiddine et al. 2015; Nakano et al. 2009). In additional research, polymerosomes were created to create a polymeric NP to interpret therapeutic stem cell MRI images in stroke patients. Due to the substantial surface area and neuroprotective qualities, nanospheres and polymerosomes are an essential part of NP.  Z-DEVD-FMK-loaded nanospheres significantly reduced infarct volume, caspase-3 activity, and nerve damage, which can be used together to treat stroke. Polymeric nanocarriers can increase the concentration of pharmaceuticals in brain tissue while avoiding phagocytosis by the reticuloendothelial system (Soppimath et al. 2001; Zhang et al. 2016). 9.5.2.1.2  Dendrimers for IS A class of artificial macromolecules known as dendrimers exhibit a structure like a tree and unique encapsulating characteristics. Interesting structural features of dendrimers include globular layers of a branched nanostructure as well as multiple terminal functional groups on the outer layer (Navath et  al. 2008). Dendrimers might cross the BBB.  Therefore, they can treat different CNS disorders (Verma et al. 2017; Gumustas et al. 2017). A unique benefit of the PEGylated dendrimers is treating stroke by decreasing the blood clots. In a mouse model of permanent focal brain ischemia, the brain could also be found to contain the optimized PAMAM formulation 24  h after injection. The PEGylated PAMAM dendrimers have the potential to be used in medication delivery systems and prolong blood circulation half-life (Srinageshwar et al. 2017; Santos et al. 2018). Another study found that the heme oxygenase-1 (HO-1) gene was effectively transported into the ischemic brain using dexamethasone-conjugated polyamidoamine generation 2 (PAMAM G2-Dexa). A biodegradable arginine ester of PAMAM dendrimer called e-PAM-R

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made it possible to efficiently transfect primary neuronal cells and post-ischemic brain with HMGB1 siRNA. “VivaGel,” a dendrimer-based medication created by Starpharma, had already completed phase I clinical trials and is intended to be used as an antiviral drug in the vagina (Kim et al. 2010; Jiang et al. 2005). 9.5.2.1.3  Nanogels for IS Nanogels are cross-linked, three-dimensional, water-soluble polymers with durable encapsulation properties that serve as reservoirs for drugs and other substances, enabling a controlled or prolonged release of the medication. Although nano gels have comparable control release features, their amorphous shape and high-water content give these formulations a larger surface area, a distinctive softness, and a higher drug-loading capacity than other DDSs. Nevertheless, thrombolysis using nano gels has been well investigated in the rat model of IS. In one of the recent studies, chitosan nano gel-loaded urokinase (UK) was stimulated using ultrasound to dissociate. In the ischemia microenvironment, PEGylated UK was employed as a nano gel polymer, which can be dissociated at low pH (Santos et al. 2022; Alkaff et al. 2020). Based on the findings, nano gels are a promising candidate for IS. 9.5.2.1.4  Micelles for IS In recent years, the value of polymeric micelles as a DDS has come to light. Amphiphilic copolymers spontaneously produce these micelles and exhibit shellcore architectures as solutions. The shell comprises hydrophilic block polymers, whereas the core consists of hydrophobic block polymers, such as L and D-line polycaprolactone. Polymeric micelles typically have particles between 10 and 100 nm in size. The loading of lipophilic medicines into the core enhances medication stability and bioavailability. After the medication has reached the target cell, the shell permits the release of the loaded drug through diffusion while protecting it from nontarget cells and serum proteins. For targeted borneol delivery, Ding et al. have created an oral polymeric micelles-based DDS (Saeedi et al. 2019; Lian and Ho 2001). Still, an intense preclinical study is needed to bring it into clinical trials. Looking over the potential, it might be one of the potential organic nanocarriers that can help treatment of IS. 9.5.2.1.5  Liposomes for IS Liposomes are artificial spherical cells that are made of single amphiphilic lipid bilayers. Based on extensive research, it is clear that liposomes can cross the BBB and remain in the bloodstream for a considerable time. Therefore, it can effectively transport therapeutic medications to brain tissue (Kraft et al. 2014; Takahashi et al. 2009). Imaizumi et  al. investigated the role of liposomes in IS.  Superoxide dismutase (SOD) is a free radical scavenger and has an inability to pass the BBB, which was delivered through the jugular vein in the form of an encapsulated liposome. Finally, infarct volume was reduced, and SOD levels were increased (Chen et al. 2010). Moreover, by altering the surface of liposomes with polyethylene glycol, the circulation period can be lengthened. The BBB disruption, increased vesicle infiltration, and prolonged accumulation at the ischemia location have all been

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linked to the formation of PEGylated liposomes in the ischemic brain. Data suggests a double-target therapy approach for IS in the middle cerebral artery occlusion (MCAO) rat model (Chen et al. 2010; Hong et al. 1997). HSP72 is only expressed in the ischemic region surrounding the infarct. PEGylated liposomes containing cytosine as the carrier and an HSP72 antibody can specifically cluster in the ischemic area and enhance the therapeutic efficacy of medications (Lasic and Needham 1995; Kawaguchi et al. 2013; Fukuta et al. 2014; Ishii et al. 2013). These favourable outcomes were also seen when neuroprotective medicines, such as VEGF (vascular endothelial growth factor), were placed into liposomes and immune-targeted at the ischemic site. Liposomes dramatically reduced the infarct magnitude and neurological impairments, which reached the brain damage area efficiently. A strokehoming peptide (SHp) that targets the ischemic regions and a transferrin receptor-derived peptide ligand (T7) increase BBB permeability and are added to the surface of liposomes. After that, the MCAO rat model’s neurological deficit, infarct size, and histological abnormalities were decreased by  the application of T7&SHp-P-L/ZL006 liposomes. Liposomes often have a high level of biocompatibility, strong drug-loading loading capacity, and excellent drug protection ability. A drawback of stroke treatment is that it has poor targeting. Research has shown that conjugating PEG, altering the surface charge, or conjugating a particular ligand might enhance the overall capacity of liposomes to penetrate the brain, thus improving the therapeutic impact (Shailendra et  al. 2014; Zhao et  al. 2016; Agulla et al. 2014). 9.5.2.1.6  Solid-Lipid Nanoparticles (SLNP) for IS SLNP is a hard fat that is stable at room and body temperature and comprises triglycerides, monoglycerides, complex glyceride mixes, waxes, and surfactant-­ stabilized triglycerides. When phospholipids are rooted through hydrophobic tail regions in the hydrophobic solid matrix that makes up the core, hydrophobic medicines are more effectively trapped there than with traditional nanocarriers. The SLNP utilized for formulation ranges in size from 50 to 1000 nm. While addressing the related individual drawbacks, SLNP combines the benefits of polymeric and liposomal nanoparticles. Thus, high physical stability, bioavailability, biocompatibility, drug protection, stringent release control, ease of production, effective tolerance, and biodegradability without producing harmful byproducts are some of SLNP’s essential qualities. The simplicity with which SLNP may traverse the BBB and their lipophilic nature make them a first-choice nano-vehicle to deliver treatment for the brain. SLNP uptake happens with processes like passive diffusion, active transport, endocytosis, and paracellular pathway via tight junction opening in brain microvasculature. Most apolipoprotein E receptors are expressed in the brain, which is significant to highlight. Hence, using this protein to functionalize SLNP might provide a potential way to enhance medication transport to the brain (Neves et al. 2017).

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9.5.2.2 Inorganic Nanocarriers for IS 9.5.2.2.1  Carbon-Based Nanomaterials for IS Due to their distinctive architectures, extraordinary properties, and widespread use, carbon-based nanomaterials have received considerable scientific attention. It has a high surface area with mechanical, thermal, optical, and electrical characteristics. These qualities have a variety of biomedical uses, including gene therapy, tissue engineering, biosensing, and medication, hormone, and enzyme administration. They cannot penetrate the BBB through passive diffusion, which suggests that these drug delivery systems have an energy-dependent mechanism. Additionally, nanomaterials made of carbon can scavenge ROS. On the other hand, it is also claimed that they produce ROS because heteroatoms are present (Teleanu et al. 2019; Amani et al. 2017). 9.5.2.2.2  Fullerenes for IS A fullerene is a zero-dimensional nanomaterial structure made of carbon that resembles a soccer ball. It is a carbon allotrope comprising C60 and C70 (Castro et al. 2017). Its form provides a unique surface chemistry that offers a substantial yet straightforward ornamentation for biomedical applications as well as highly relative to radical species (Monti et al. 2000; Liu et al. 2017a, b). A fullerene can also react with superoxides due to this catalytic ability without being harmed. Its capacity to spread electrons through a 3D conjugated structure and absorb them offers it antioxidant properties. Fullerenes function as “free radical sponges’ because of their micromolar concentrations, which aid in eliminating superoxide anion and H2O2 (Hsieh et al. 2017; Lin and Lu 2012). According to research, apoptosis’s activating stage of mitochondrial membrane breakdown and leaking is prevented by carboxy fullerene. Several fullerene derivatives are applied widely to ischemic tissue to reduce ROS and preserve tissue function following ischemia (Lin and Lu 2012). Thompson et  al. described an expansion of the myocardial infarction and contraction of the coronary arteries when C60 fullerene is delivered intratracheal or intravenously (Kazemzadeh and Mozafari 2019). Fullerene has been used extensively for medicinal delivery to the brain due to its antioxidant properties. Fullerene successfully traverses the BBB if combined with a physiologically active component, making easy work of targeted drug delivery (Henna et  al. 2020; Dellinger et al. 2013). 9.5.2.2.3  Graphene for IS Graphene has an excellent performance profile in light-controlled drug release and photothermal therapy, which can increase BBB permeability (Mohanty and Berry 2008). Graphene’s delocalized electrons make binding with different pharmacological molecules easier using a modified version of Hummers’ approach (Mendonca et al. 2016). In vivo, tests proved that drug-loaded functionalized GO could effectively aggregate in the mouse brain. In contrast to untreated rGO, which exhibited little toxicity, PEG-modified rGO caused considerable toxicity in primary rat astrocytes. In contrast to the latter, the former has only mild levels of the cell body and

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process retraction, absence of contact among cells, and an entire lack of standard cellular structure. Research studies verified that PEG-rGO could produce more ROS in cells than rGO, which may cause PEG-rGO toxicity. The size of rGO and PEGrGO is 342  nm and 910  nm, respectively, and these sizes may show substantial variations. After ischemia, rGO can enter the hippocampal area through blood circulation due to a temporary reduction in the BBB’s paracellular tightness. BBB quick opening caused by rGO did not demonstrate severe negative impacts. Drug distribution to the lesion site may be assessed thanks to rGO’s capacity to boost BBB permeability momentarily. BBB permeability was increased after utilizing rGO, highlighting the significant potential of graphene group materials in treating brain disorders (Mendonça et al. 2015; Fernandes et al. 2018). 9.5.2.2.4  Carbon Nanotubes for IS Carbon-based nanostructures with a cylindrical shape are called carbon nanotubes (CNTs), which may be single-walled and multiwalled CNTs, depending on the number of layers. Due to their distinctive chemical, mechanical, and electrical qualities, these are helpful medical tools. The creation of hybrid nanotube-neural networks that support neuronal activity, network communication, and synapse formation has been demonstrated by evaluating pure and modified versions of CNTs. Because CNTs and stem cells continue to interact, a novel application is designed producing neural tissue through cellular stimulation. Kafa et al. demonstrated in an animal model using a scanning electron microscope that a significant amount of CNTs accumulates in the brain tissue and is taken up by astrocytes as well as it was also noted that these nanostructures permeability decreased as the temperature rose (Karthivashan et al. 2018; Kafa et al. 2015). 9.5.2.2.5  Quantum Dots for IS Quantum dots have drawn much attention from scientists because of their optical and electrical properties (Ghosh et  al. 2022; Thukral et  al. 2023). Quantum dots have emerged as nanoscaled systems for imaging, diagnostics, and transplanted tagged cells for tracking. However, quantum dots need to undergo secondary surface functionalization for brain targeting and BBB crossing to be viable. Hence, penetrating the brain parenchyma involves carrier-mediated transport pathways (Granada-Ramírez et al. 2018; Aswathi et al. 2018).

9.5.2.3 Biological Vectors for IS 9.5.2.3.1  Viral Vectors for IS The host cell is no longer helpful as a viral vector because viruses can enter and insert genetic material there. A standard copy of the gene is delivered by using viral vectors in the CNS to reduce the harmful functions of a faulty gene. The two primary methods for delivering viral vectors into the brain are transitory rupture of the BBB and receptor-mediated routes that cross endothelial cells. One form of disruption is the intravenous delivery of mannitol solution, which leads to the osmotic shrinking of cells. Several studies have demonstrated the effectiveness of herpes

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simplex viral vectors in preventing stroke by repairing or replacing genes that harm neurons. Because of the dangers of using adenovirus-mediated vectors and the high likelihood of failure, comparable results were obtained (Hunter et  al. 2017; Choudhury et al. 2017). 9.5.2.3.2  Extracellular Vesicles for IS Extracellular vesicles (EV) are a group of diverse membrane structures generated from cells. EVs play various roles in intercellular communication, exchanging protein, lipid, and genetic material throughout the body. EVs can potentially cross the BBB by adsorption- or receptor-mediated transcytosis. It is yet unclear strictly how physiological and pathological disorders can be relieved. It has been shown that intranasal delivery of curcumin-containing exosomes can reduce autoimmune reactions and brain inflammation (van Niel et al. 2018; Matsumoto et al. 2017; András and Toborek 2015).

9.6 Intranasal Administration for IS Oral and parenteral routes of administration are used by multiple medications used to treat CNS illnesses like Alzheimer’s disease (AD), Parkinson’s disease (PD), as well as IS. However, because of the shorter half-life of the delivered medications and struggle against BBB permeability, such routes possess a significant disadvantage in that they have constrained the availability of drugs to the brain. With the IN route, such restrictions are easily bypass as the medication is administered from the nose directly into the deep areas of the brain, avoiding the BBB (Brasseur et  al. 1980; Kreuter 1994; des Rieux et al. 2006). Also, it has been asserted that using the IN route makes systemic medication distribution less complicated and improves the entire administration process, making it the finest noninvasive choice. As the sole area of the brain without BBB protection, the olfactory-neuro epithelium is the quicker and more straightforward approach to breaching the BBB (Alavian and Shams 2020; Yadav et al. 2018; Tao et al. 2013; Zhang et al. 2010). Three paths are used when a medication is delivered to the target brain via the IN route. Drugs can be delivered through the olfactory pathway, which avoids the blood-brain barrier; the trigeminal pathway, which goes from the olfactory bulb to the brain stem; and the vascular pathway, which crosses the BBB by travelling through the lungs. However, the IN route may have drawbacks such as a shorter residence duration, nasal irritability, difficulties conveying high molecular weight medications, and access to only certain parts of the brain. Since NP-based drug delivery increases drug-loading capacity and bioavailability, it is particularly effective and suited for IN administration of medicines. Recent research has examined the effectiveness of anti-inflammatory and anti-oxidative medications encapsulated in NPs to treat neurological conditions such as IS and AD (Uner and Yener 2007; Fundarò et al. 2000; Arora et al. 2002). Polymeric nanoparticles with chitosan-based, SLNP, and PEGPLGA coatings are frequently utilized for direct drug administration from the nose to the brain. In their study, Ahmad et  al. (2016) showed how to manufacture

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rutin-encapsulated chitosan-based NPs. When delivered via the IN route in the MCAO rat model, these NPs significantly improved rats’ brain-targeting efficiency, drug bioavailability, and locomotor activity post-ischemic stroke (Ahmad et  al. 2016). SLNP has recently gained recognition as a fantastic substitute for simple transmucosal medication delivery. The capacity of SLNP to interface with the mucosal epithelium and facilitate transmucosal transport as drug carriers is frequently enhanced by coating the surface of the particle with hydrophilic materials like PEG (Ahmad et al. 2013). Different routes of drug administration are shown in the form of Table 9.1.

9.7 Nasal Drug Delivery in IS In modern times, there is development of novel techniques for direct drug delivery from nose to brain. The medicine will be applied to the trigeminal nerve-rich region of the nose or the olfactory epithelium to facilitate delivery to the brain via the trigeminal or olfactory pathways. Recently, researchers have developed several effective, innovative medication delivery systems to carry out the same. Clinical access has been possible for atomizers, nebulizers, pressurized meter dosage inhalers, olfactory delivery systems, and powdered devices (Ahmad et al. 2013, 2016). These items are additionally divided into three classes: powder, liquid, and semisolid formulations, which are discussed in Table 9.2.

Table 9.1  Major drug administration methods for treating neurological disorders Route of administration Oral

Intravenous

Intranasal

Intracerebral

Rectal

Advantages Easy to administer Easy to administer high doses Easy adsorption Direct delivery No first-pass effect Complete drug stability Bypass first-pass effect Complete drug stability Direct delivery Direct delivery into the suitable brain region Fast drug release and effect Steady release of drug Bypass first-pass effect

Disadvantages Nausea First-pass effect Slow release of drug Inconvenient Not safe Risk of infection Suitable for low molecular weight drugs Hard in dose precision and regulation High risk of infection

Irregular and slow adsorption rate

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Table 9.2  Different devices for targeting the brain via nasal drug delivery system Powder devices

Intranasal mode of delivery

Interact with nasal mucosa for longer periods of time

Dry powder inhaler

Intranasal mode of delivery

Drug particulates, either suspended or dissolution of the drug, occur on contact with nasal mucosa

Liquidbased devices

Delivered in the form of nasal sprays, nasal drops, and metered nebulizers

Drugs in liquid formulations easily get washed from nasal mucosa due to mucociliary action

Direct drug delivery to the olfactory region The drug is in a tube/straw and attached with a syringe, but local anaesthesia is required •  Single-use and delivered in small doses •  Mono-dose inhalers are single-unit syringes, whereas accurate drug dosing is multi-dose inhalers •  Nasal powder inhaler suitable for low- and high-molecular weight drugs and suitable for systemic delivery •  Absorption enhancers are not needed in nasal powder sprayers •  Catheters are used for delivering liquid formulations, but the risk of mechanical injuries persist • Drops •  Squeeze bottle •  Metered-dose spray pumps •  Pressurized olfactory device •  Nebulizers and atomizers

9.7.1 Toxicity Risks of Nanocarriers in IS Nanocarriers are a powerful instrument for entering the BBB, but they have several problems that must be resolved. First, little research has been done on how the substance spreads in the brain after ingestion, which makes nanocarriers quite dangerous for the brain. Even the brain has trouble metabolizing inorganic materials like silica or gold nanoparticles, which can lead to neurodegeneration (Neetika et  al. 2023; Chaudhary 2022). Biodegradable nanoparticles have also been linked to neurotoxicity in research studies in the case of a dose-dependent injection of chitosan nanoparticles treated with polysorbate 80 for 7 days, which reduced body weight with neuronal apoptosis and necrosis a mild inflammatory response in the frontal cortex. The administration mode of nanocarriers is one of the major problems. It would be considerably simpler for individuals with neurodegenerative illnesses to receive nano-formulations in oral dose forms, as most are injections. Consequently, more investigation is required into acute toxicity and long-term neurotoxicity (Niu et al. 2019).

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9.8 Conclusion and Future Directions IS is a disruption in the blood flow, which causes brain injury. Still, there is not a single drug available to treat IS except t-PA, and we need to figure out a drug or promising therapy for IS. An appealing strategy for addressing various cascades of IS is nanomedicine therapies. NPs are an excellent option due to their stability, BBB penetration, and better blood flow. For pharmaceuticals to be effective, they must cross the BBB and reach the ischemic zone. Nanomedicines based on liposomes, nanoparticles, and hydrogels can cross the BBB and transport medications to the lesion, which might have the potential to treat IS. Peptides and surfactants can facilitate drug administration by increasing BBB permeability; it also carries a higher risk of facilitating the transfer of harmful substances into the brain. Thorough research investigations are required before nanomedicine can be used for IS. After administration of nanomedicines, we need to observe adverse effects, and we need to shed more light on the transition from preclinical to clinical applications.

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Raman Spectroscopy for Detecting Neurological Disorders: Progress and Prospects

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Mithun N, Megha Sunil, Meril Charles, Sanoop Pavithran M, Santhosh Chidangil, and Jijo Lukose

Abstract

Raman spectroscopy (RS) is recognized as a highly sensitive and label-free technique capable of providing biochemical information about cells, tissues, and body fluids. The application of RS in neuroscience to investigate human saliva, serum, and blood components for disease diagnosis has been intensively studied, and it has recently acquired significant clinical interest, particularly when combined with artificial intelligence and machine learning algorithms. This chapter provides an in-depth exploration of RS and its variant techniques, encompassing Raman tweezers, surface-enhanced Raman scattering (SERS), coherent antiStokes Raman scattering (CARS), and resonance Raman spectroscopy (RRS), which holds a crucial and noteworthy role in the advancement of neuroscience research. The weak Raman signals obtained from clinical samples such as saliva and serum via conventional Raman spectroscopy are low enough for diagnostic purposes. In the SERS approach, the targeted analytes that have been adsorbed on metal colloidal nanoparticles or nanosubtrates experience substantially higher Raman scattering efficiency, ultimately resulting in the development of a noninvasive diagnostic pathway for detecting various neurological disorders  (ND). Recent advancements in nanotechnology and cost-effective fabrication routes for generating nanostructures with tailor-made morphologies have contributed significantly to developing a wide variety of SERS nanosubstrates for sensing purposes. Raman tweezers represent a powerful integration of Raman spectroscopy and optical tweezers techniques. It enables the noncontact optical trapping of micron-sized particles suspended in physiological media, allowing the acquisition of Raman spectra at the level of individual cells. This innovative approach M. N · M. Sunil · M. Charles · S. P. M · S. Chidangil · J. Lukose (*) Centre of Excellence for Biophotonics, Department of Atomic and Molecular Physics, Manipal Academy of Higher Education, Manipal, Karnataka, India e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_10

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holds promise in the field of ND diagnosis and research. This chapter discusses the advancements in the exploration of different RS techniques for the identification and prediction of diseases from body fluids and tissues with a focus on neurological disorders. In addition, the potential utilization of Raman spectroscopy in neurosurgery is also discussed. This chapter concludes with the existing challenges to exploit this technology from bench to bedside as well as its possible future applications as a viable clinical diagnostic method for neurological illnesses. Keywords

Raman spectroscopy · Surface enhanced Raman spectroscopy · Neurological disorders · Nanoparticle · Tissue · Blood · Saliva

10.1 Introduction Neurological disorders refer to a broad spectrum of conditions that influence the central nervous system, which consists of the brain, spinal cord, and peripheral nerves distributed throughout the body. These disorders can result from structural abnormalities, metabolic disturbances, or issues with electrical signalling in the neuron system (Siuly and Zhang 2016). Conditions like epilepsy, Alzheimer’s disease (AD), various forms of dementia, vascular brain diseases such as stroke, migraines, multiple sclerosis, Parkinson’s disease (PD), neuroinfections, brain tumours, trauma-induced nervous system disorders resulting from head injuries, and neurological disorders triggered by malnutrition are all examples of such conditions (World Health Organization 2016). The global burden of neurological diseases is rising together with the proportion of people over 65 years. Millions of individuals throughout the world experience neurological problems. Each year, over six million people experience a stroke, with more than 80% of death reports. Worldwide, there are over 50 million people who have epilepsy (World Health Organization 2022). As per the World Health Organization (WHO), dementia represents a substantial global health issue. Currently, approximately 55 million individuals worldwide are affected with dementia. It is anticipated that by the year 2030, the number of dementia sufferers will rise to 78 million, and by 2050, this figure is projected to further increase to 139 million (World Health Organization 2021). Additionally, AD stands as the primary cause of dementia in the world, representing approximately 60–80% of all dementia cases. AD is an increasing neurodegenerative condition that primarily impacts memory, cognitive functions, and behaviour (Harper 2020). As per the National Library of Medicine, there are approximately 600 different neurologic diseases identified in the United States (DPHHS n.d.). Patients and their families are frequently distressed by neurological disorders, leading to a lowering of the quality of patient’s life. Fast and precise diagnosis of these illnesses can play a crucial role in saving and significantly improving patients’ lives. Various diagnostic tools and imaging techniques are utilized in the detection,

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management, and treatment of neurological diseases (Chaudhary et al. 2023). These include electroencephalography (EEG), computerized tomography (CT scan), magnetic resonance imaging (MRI scan), electromyography (EMG), arteriograms (angiograms), and positron emission tomography (PET scan or PET imagery) (Siuly and Zhang 2016; Young et al. 2020). These advanced technologies are crucial in assisting physicians in diagnosing the existence of neuro disorders. The most commonly employed diagnostic tools for neuro disorders include MRI, X-ray computed tomography, and PET (Gautam et al. 2022). While these technologies can photograph deep tissues, they have limitations, such as high costs, poor spatial resolution, limited access to exact chemical data, and dangerous ionizing radiation side effects (Doruyter et al. 2021). Researchers were also keen on developing biomarker panels to enhance the precision of diagnosing neurodegenerative diseases (Chaudhary et al. 2023). However, these techniques require costly, invasive, and time-­consuming technologies, such as imaging and cerebrospinal fluid tests. Consequently, there is a strong focus on developing rapid, noninvasive, and cost-effective procedures to address these challenges in clinical applications. In contemporary times, exploring biomolecule behaviour and metabolism at the molecular level has assumed a central role across diverse scientific disciplines, such as biomedicine and pharmaceuticals. Molecular-level investigations hold significant importance for advancing medical diagnostics, drug development, the progression of biotechnologies, and various other fields. Existing conventional techniques, including immunoassays, optical microscopy methods, and fluorescence spectroscopy, are constrained by their limited specificity in findings. Moreover, these methods yield minimal insights into molecular-level details. This is where the significance of Raman spectroscopy becomes evident. RS, being a label-free technique, stands out for its exceptional specificity, offering comprehensive details about the molecular compositions and structures of the samples under examination (Petry et al. 2003). The advancement of diverse light sources, portable detectors, and machinelearning algorithms has allowed large-scale studies on spectroscopic approaches for clinical applications. RS, an inelastic light scattering-based technique, can yield biochemical information about biological materials such as tissue, cells, and body fluids in label-free conditions (Taha et al. 2023). Numerous studies have shown that RS has the capability to diagnose individuals with a variety of degenerative diseases, including dementia, Parkinson’s disease, and brain tumours. Raman’s studies have been successful in providing valuable insights regarding these illnesses utilising less invasive samples, such as bodily fluids. This can make sample collection and subsequent analysis easier and more convenient for patients (Paraskevaidi et al. 2018). RS does not require sophisticated and complex instrumentation and only needs to have minimum consumables, which makes the device translatable. Despite the benefits of the Raman spectroscopic technique, the utility of conventional Raman spectroscopy in body fluid analysis is sometimes hindered, primarily due to its weak Raman signal strength, causing low sensitivity for such samples. Consequently, there is a high necessity to enhance sensitivity and Raman signal intensity for the effective implementation of this spectroscopic modality for biomedical applications. Advancements in nanoscience and nanotechnology have led

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to the fabrication of diverse nanoparticle-based sensing modalities in a variety of sectors, including disease detection, food adulteration, water contamination, etc. In a similar fashion, converging different forms of nanoparticles/nanosubstrates with the Raman spectroscopic technique termed surface-enhanced Raman spectroscopy (SERS) emerged as a reliable approach that can resolve the detection challenges linked with relatively weak Raman scattering. Combining nanoparticles not only preserves the advantages of conventional Raman spectroscopy but also augments sensitivity while effectively reducing fluorescence interference (Bantz et al. 2011). This is an exceptionally powerful tool that merges advanced laser spectroscopy with the distinctive optical characteristics of metallic nanostructures (Sharma et al. 2012; Ding et al. 2017; Kneipp et al. 2002). When molecules are attached to or located near nanometer-sized metallic particles, SERS generates significantly stronger Raman signals. This increase in Raman signal intensity is attributed to both electromagnetic and chemical mechanisms. When molecules are bound to or located in proximity to nanostructured metal surfaces, often composed of silver or gold, the incoming light triggers a collective oscillation of electrons in the conduction band of the metal. This oscillation gives rise to localized surface plasmons on the metal surface. These plasmonic fields are highly concentrated and amplified at the nanoscale features of the metal surface, such as roughened surfaces, nanoparticles, or nanogaps. Currently, a diverse array of methods and procedures are being used for the fabrication of SERS substrates (Lukose et al. 2023). The process of creating SERS substrates through plasmonic colloidal particle assistance involves the clustering of analyte molecules (Shiohara et al. 2020). The points where the particles meet are called hotspots, generating strong localized electromagnetic fields that enhance Raman scattering for detecting the analyte samples. For instance, particles with irregular shapes, such as nanostars or nanorods, generate stronger fields at sharp edges and corners, resulting in enhanced signal strength for the molecules located in those areas (Hrelescu et  al. 2009). Gold nanorods are favoured due to their capacity to alter their aspect ratio, leading to shifts in surface plasmon bands and diverse applications (Xu et al. 2012; Kim et al. 2013). In the context of nanostars, the spikes on their surface act as efficient nanoantennas, generating substantial electromagnetic field enhancement at each tip’s edge (Khoury and Vo-Dinh 2008). This, in turn, generates numerous hot spots within a single nanoparticle. Thus, the SERS technique has found high potential in biomedical applications, including neurological diseases, owing to its rapid sensing with high sensitivity. In this chapter, we make an effort to clarify important cutting-edge RS developments in the area of neuro disorders. The fundamentals of the Raman scattering process and a brief description of various Raman methods, including Resonance Raman spectroscopy (RRS), SERS, and CARS, serve as the topics of our discussion. Following that, we give a brief overview of the progress made thus far using RS as a valuable technique for studying brain illnesses. This comprises the application of RS to acquire characteristic spectral fingerprints from blood, saliva, tears and tissues for diagnostic and surgical demarcation.

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10.2 Basic Overview of Raman Spectroscopy In recent times, RS has emerged as a powerful technique with broad applications across various areas of natural science. Raman effect has been consistently shown in recent years as a very flexible method that may be used in almost every area of research. Raman spectroscopy has several benefits, including its high specificity and adaptability. It is a nondestructive method that typically requires very little to no sample preparation. It is possible to measure solid, liquid, and gaseous samples as well as transparent or opaque samples and samples with various surface textures (Schmitt and Popp 2006). RS is a commonly employed method that enables the analysis of a molecule or compound’s structural and chemical properties through the measurement of its vibrational states from Raman scattered light. When a monochromatic light is directed at a material, most of the light passes through the material without any change in frequency. However, some light beam is scattered with frequencies that are either lower or higher than the incident frequency. The phenomenon in which scattered radiation exhibits a change in frequency is referred to as Raman scattering, commonly known as the Raman effect (Banwell and McCash 2017). The major share of the scattered radiation has a frequency as that of the incident radiation, resulting in Rayleigh scattering. Stokes scattering refers to the process where Raman-shifted photons have lower frequency or longer wavelengths than the Rayleigh line. Anti-Stokes scattering occurs when Raman-shifted photons have frequencies higher than the Rayleigh line. Figure  10.1 illustrates the processes of Stokes-Raman scattering, anti-Stokes-Raman scattering, and Rayleigh scattering (Liu et al. 2022). Figure 10.3a shows the energy level diagram of Raman scattering (Liu et al. 2022). In conventional RS, the Stokes spectrum is typically studied more

Fig. 10.1  Raman and Rayleigh scattering (Liu et al. 2022)

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extensively than the anti-Stokes line. This preference is because the Stokes spectrum generally exhibits a higher intensity, making it easier to detect and analyse compared to the anti-Stokes line (Kauffmann et  al. 2019). The Raman spectrum represents the intensity of scattered light concerning the Raman shift, which signifies the frequency change relative to the Rayleigh line (the incident light frequency). Although RS has a very high specificity, only a part of incident photons is inelastically scattered, limiting the ability to identify molecules at deficient concentrations. The most commonly used techniques to overcome this limitation are RRS and SERS in the case of linear RS. For nonlinear RS, the popular methods are stimulated Raman scattering (SRS) and CARS. These techniques allow the examination of low-concentration materials by significantly enhancing the weak Raman signals by several orders. Moreover, incorporating Raman spectroscopy with the microscope has paved a new way for understanding the microworld with greater accuracy and precision. The Raman tweezer enabled us to capture micron-sized cellular components and perform real-time evaluation of biochemical features.

10.3 Resonance Raman Spectroscopy RRS is a better method employed to study the vibrational and electronic structures of chromophoric chemical systems. In this method, when the wavelength used to generate Raman scattering falls within the electronic absorption band, the vibrational modes which are associated with the electronic transition are amplified by a factor of up to 106 compared to nonresonant excitation (Schmitt and Popp 2006). This is the resonance condition in resonance RS and significantly enhances the probability of incident photons interacting with the molecule (Czernuszewicz and Zaczek 2008). In RR spectra, the vibrational bands primarily correspond to molecular groups that are electronically resonant with chromophores. As a result, the overall RR spectrum involves fewer vibrational modes compared to the nonresonant Raman spectrum. Chromophores must be present in the molecules in order to conduct RR spectroscopy, and the wavelength should be adjusted to coincide with the analyte’s electronic absorption. Figure 10.3b illustrates the energy level diagram of resonance Raman spectroscopy (Orlando et al. 2021). However, there are certain limitations to RR spectroscopy. First, it is essential to consider that molecules excited through electronic absorption can undergo rapid photodegradation, and fluorescence may be simultaneously excited (Cialla-May et al. 2021).

10.4 Surface-Enhanced Raman Scattering The SERS technique utilizes nanostructured surfaces or materials to amplify the Raman scattering signals from molecules that are either adsorbed on the surface or in close proximity to it (Stiles et al. 2008). During the initial phases of SERS development, various enhancement mechanisms were proposed. Nonetheless, at present,

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Fig. 10.2  Schematic of SERS (Yin et al. 2022)

only two mechanisms enjoy widespread acceptance, namely, the electromagnetic theory and chemical enhancement theory (Cong et al. 2020). When the molecules are positioned within the intense electromagnetic field of the surface plasmons, the electric field experienced by the molecules is significantly amplified. This electromagnetic enhancement factor can be so high that even single molecules can produce measurable Raman signals (Sharma et al. 2012). In addition to the electromagnetic enhancement, a chemical enhancement mechanism is also observed in SERS (Fig. 10.2). This mechanism is based on the charge transfer or chemical interactions within the adsorbed molecules and the metal surface. The SERS effect is observed as an increase in Raman scattering of a molecule with a factor of up to 1011–1014. SERS is realized using a suitable metal substrate with nanostructured features to support the generation of localized surface plasmons. Commonly used metals include silver, gold, and copper, which exhibit strong plasmonic properties in the visible and near-infrared regions. The metal substrate can take various forms, such as nanoparticles, nanospheres, nanorods, nanostars, or roughened metal surfaces. Techniques such as chemical reduction, electrochemical deposition, or laser ablation can be employed to fabricate nanostructured metal surfaces. The molecules of interest for analysis are then attached to or positioned close to the nanostructured metal surface. This can be achieved through direct deposition, immersion of the metal substrate in a solution containing the analyte, or by dropcasting the analyte solution onto the metal surface (Demirtaş et al. 2020). Noble metals are expensive, difficult to manufacture on a large scale, uneven in reproducibility, and unstable over lengthy periods of time (Chen et al. 2020). These characteristics make them a poor choice for highly developed SERS nanosubstrates. A variety of two-dimensional (2D) nanomaterials have become an effective substitute to overcome these restrictions. The remarkable physical and chemical properties of 2D nanomaterials, which have drawn growing interest, make them appealing. These nanomaterials can behave as metallic, semiconducting, magnetic, or nonmagnetic, depending on their altered compositions. Simple synthesis, significant certain surface areas, outstanding mechanical properties, exceptional optical qualities, and favourable biocompatibility are only a few of the benefits of 2D nanomaterials and their composites. These characteristics make it possible to use them

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practically to improve SERS and provide a workable answer to the problems that metallic nanosubstrates provide, like high costs, prominent metal-adsorbate interactions, catalytic impacts, and photobleaching events. A variety of 2D nanomaterials have since been investigated as substrates for SERS applications. Graphene and MXenes are 2D nanomaterials that are widely used for the fabrication of SERS nanosubstrates (Liu et  al. 2023). Graphene can be readily made through mechanical or chemical exfoliation of graphite, and its presence can be distinctly discerned using optical microscopy on a SiO2/Si substrate (Ling et  al. 2010). The phenomenon known as graphene-enhanced Raman spectroscopy (GERS) was initially documented by Ling et al. In this work, mechanically exfoliated graphene was deposited onto a SiO2/Si substrate, and then organic molecules were applied to the graphene surface. MXenes represent a fresh class of two-dimensional materials produced by selectively removing layers from MAX phases (He et al. 2022). These MXenes bring together the impressive electrical conductivity inherent in transition metal carbides/ nitrides and the water-attracting attributes of their terminal surfaces, leading to distinctive electronic and optical characteristics. Two-dimensional variations of MXenes show great potential as attractive candidates for substrates in SERS, primarily because of their metallic conductivity and abundant surface terminations. Scientific studies have documented the simple synthesis of a bimetallic solid solution known as TiVC (MXene) and its effectiveness in SERS applications. The fabrication of few-layered MXene nanosheets with robust crystalline qualities has been effectively accomplished using a simplified chemical etching procedure, bypassing the need for ultrasonic treatment and the introduction of organic solvents. The SERS capability of this engineered MXene was explored by constructing a self-supporting TiVC film as the base. This resulted in attaining a SERS enhancement factor reaching 1012, alongside successfully validating detection limits at the femtomolar level. SERS nano substrate with attributes of low limit of detection (LOD), enduring stability, and uniformity has been introduced, centred on unmodified Ti3C2Tx (Liu et al. 2020). An adapted synthesis method has been devised to generate expansive and monolayered Ti3C2Tx nanosheets. These nanosheets, derived through the etching of the Ti3AlC2 phase using LiF/HCl, were employed as nanosubstrates for SERS, showcasing the capability to detect dye molecules at a minimal LOD. Ti3C2Tx nanosheets can be prepared through etching and subsequently undergo surface modification via dye molecules. Following this preparation, the nanosubstrates were submerged in diverse concentrations of ethyl alcohol solutions containing dye molecules for an extended period and subsequently cleansed with absolute ethanol to eliminate unbound dye molecules prior to SERS analysis. Utilising Ti3C2Tx nanosheets as SERS nanosubstrates was motivated by their substantial adsorption surface area, coupled with the benefits of a straightforward fabrication process and reduced expenses. This SERS nanosubstrates provide a minimal limit of detection (LOD) for probe dye molecules, showing the efficacy of 2D nanomaterials in this regard.

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Utilising readily obtainable polyvinylidene fluoride (PVDF) and nylon flexible membranes, enhanced with a coating of silver (Ag) nanoparticles and reduced graphene oxide (AgNP/rGO) nanocomposites through vacuum filtration, presents a superior approach to crafting SERS nanosubstrates (Çelik et al. 2023). The threedimensional porous structure inherent in these nanosubstrates can provide rapid SERS measurements. The combination of graphene oxide and Ag nanoparticles results in nanohybrids, which can be synthesized by reducing a mixture of Ag nitrate and graphene oxide (GO) in water, utilizing the gentle reducing agent ascorbic acid (Kasztelan et  al. 2021). This includes influencing both the configuration and quantity of Ag nanostructures developed on the layers of GO, subsequently enhancing the efficiency of SERS. Graphene oxide nanoribbons (GONRs), derived via the oxidative unzipping of carbon nanotubes, possess applicability in SERS (González-Domínguez et  al. 2019). Introducing chemical functionalization to these GONRs by attaching terminal thiol groups facilitates a remarkably robust interaction between GONRs and gold nanoparticles (AuNPs). This interaction is accompanied by the creation of clusters of two-dimensional AuNPs, yielding a favourable impact on SERS outcomes. The presence of thiol terminal groups has a pivotal role in arranging AuNPs onto the GONR surface in a bidimensional configuration. This innovation paves the way for prospective designs that could evolve into valuable SERS platforms, serving as active substrates for SERS applications. A fresh platform aimed at enhancing SERS-based chemical sensors can be devised by employing 3D microporous graphene foam (GF) adorned with Ag nanoparticles (Srichan et al. 2016). The outcomes reveal a pronounced augmentation of the SERS effect within a multilayer graphene foam (GF) structure, achieved by the incorporation of silver nanoparticles. This enhancement is notably substantial, as the AgNP/GF sensor demonstrates a SERS enhancement factor of four orders which is higher than that observed with an AgNP-coated silicon (Si) nanosubstrate.

10.5 Coherent Anti-stokes Raman Scattering Coherent Raman scattering (CRS) is a type of nonlinear Raman technique that allows label-free imaging and spectroscopy of biological samples and other materials. It offers valuable information about the chemical composition and spatial distribution of molecules without requiring external markers or dyes. In a typical CRS experiment, two or more laser beams are used to excite the sample. These laser beams have specific frequencies and are carefully controlled to ensure that they are in phase with each other at the point of interaction with the sample. When these coherent laser beams interact with the sample, they can induce or stimulate molecular vibrations that match the frequency and phase of the incoming light waves. The most popular method, however, is CARS (Cheng and Xie 2004; Vlasov et al. 2020). The Stokes beam and the pump beam are the two types of laser beams employed in

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A Spontaneous Raman

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Fig. 10.3  Schematic energy level diagrams for (a) spontaneous Raman, (b) stimulated Raman scattering (SRS), and (c) coherent anti-Stokes Raman scattering (CARS) processes (Tipping et al. 2016)

CARS. The frequency of the Stokes beam is adjusted to be lower than that of the pump beam. The two beams’ frequency difference is adjusted to coincide with a certain vibrational frequency of the sample’s molecules of interest (DePaoli et al. 2020). Therefore, a high number of excited molecules can be pumped to a higher virtual state by the pump frequency, where they can subsequently de-excite and produce strong anti-Stokes Raman lines by returning to the ground state. The energy level diagram of CARS is given in Fig.  10.3c. The sensitivity of the process is 105–1010 times higher than that of the conventional RS.

10.6 Stimulated Raman Scattering In SRS, the intensity of Stokes emission is enhanced with two components: a pump and a Stokes beam, with slightly different frequencies (Fig. 10.3b). When the two beams interact with the sample, they create a signal beam with a frequency corresponding to molecular vibrations. In the presence of resonance, a significant signal enhancement known as stimulated Raman gain (SRG) is observed, which occurs when the frequency difference aligns with the disparity in energies between the ground and the excited states. The strength of the signal beam is directly correlated with the amount of the target molecule present, allowing quantitative imaging of specific molecules (Vlasov et al. 2020). The incident laser strength must be at least several megawatts to produce detectable stimulated Raman scattering (Wang 1969).

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10.7 Raman Tweezers A single molecule, cell, or microorganism is trapped or kept in the radiation path during the spectroscopic interrogation using the laser tweezing or laser trapping technique (Fazal and Block 2011). An optical tweezer uses a laser beam to manipulate minuscule objects. To concentrate a laser beam on a particular region of the sample plane, a microscope objective with a large numerical aperture is utilized. This region turns into an optical trap that can contain particles with sizes as small as a micrometre. The intensity profile of the trapping laser has a Gaussian profile in a typical tweezer system setup. The light at the centre of the beam is more intense than that at the edges. The laws of reflection and refraction are applied to the light’s rays when they encounter the microparticle. The combined forces of these rays can be divided into two parts: the gradient force and the scattering force. When the scattering force contribution from refracted rays surpasses that of reflected rays, a stable optical trap is formed along the z-axis. This creates a restoring force that pulls the micron-sized particle towards the centre along the x-y plane. Figure 10.4 illustrates the direction of the gradient and the scattering force acting on a dielectric micronsized particle positioned in a laser focal spot with a Gaussian intensity profile (Zaltron et al. 2020). The gradient force must be much greater than the scattering force to produce stable optical trapping. The Raman tweezers technique combines optical tweezers and Raman spectroscopy on a single platform and is used for single, live-cell spectroscopy. Raman scattering measurements can be made in an optically trapped cell suspended in a suitable physiological solution using Raman Fig. 10.4  Two types of forces on a dielectric particle placed in a laser spot with a Gaussian intensity profile (Zaltron et al. 2020)

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tweezers. A single laser or two lasers can be used to perform simultaneous measurements for both trapping and spectroscopy. Raman tweezers were used to study the external stress on RBCs caused by different agents, such as bisphenol-A, intravenous fluids, ethanol, and nanoparticles (Lukose et al. 2019a, b, c; Barkur et al. 2020; Mithun et al. 2021).

10.8 Raman Spectroscopy for Body Fluid-Based Investigations Raman spectroscopy is a highly effective analytical method used to examine biological samples, encompassing blood cells, plasma, tissues, saliva, tears, and more. This well-established technique proves particularly valuable for investigating neurological disorders. Blood samples can be used for detailed studies of disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia. Patients with AD will slowly decrease their memory power and destroy their thinking skills.

10.8.1 Detection from Platelets The cerebral amyloid angiopathy (CAA) subtype of AD is the development of neurotoxic amyloid-ß plaques in the cerebral blood vessels and brain parenchyma (Gowert et al. 2014). AD has a close connection to vascular conditions, including atherosclerosis and stroke. Alzheimer’s patients experience cerebral vascular dysfunction, which alters blood flow and may be a major factor in the pathophysiology of the condition, which includes neuronal death and memory problems. The main participants in haemostasis and thrombosis are platelets; however, they also have a role in neuroinflammatory illnesses such as AD.  Due to their ability to produce amyloid-ß (Aß) peptides through enzymatic activity, platelets have long been used as a supplementary reference to study the pathogenesis of AD. Additionally, platelets can be considered a biomarker for the detection of AD. The Raman spectroscopy technique combined with a multilayer perceptron network can be applied for the early diagnosis of AD (Chen et al. 2011). Mouse models can be used for studying this disease condition. The Raman marker band of platelets at 740  cm−1 corresponding to the proteinic side chain structure has an increased intensity in AD. Additionally, the band at 1654 cm−1 of the amide I band of the protein α-helix structure has a decreased intensity in Alzheimer’s patients. Aron Park et al. employed RS in conjunction with the feature selection approach to successfully diagnose AD (Park et al. 2013). They studied the Raman spectra of platelets obtained from Alzheimer’s patients and healthy individuals. For the feature selection technique, the most significant bands from the pre-processed spectra were selected as feature candidates. To determine the coefficient correlation between the reference band and the chosen bands, the most differentiating band was chosen as the reference. To decrease the potential feature candidates, the strongly associated characteristics were removed. The peak intensity at 1658 cm−1 and intensity ratio of

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757 and 743 cm−1 were determined to be the two best characteristic signatures for the identification of AD based on the analysis. The classification results for the multilayer perceptron (MLP) reveal a classification rate of 95.8% using these two characteristics. Another group of researchers examined AD from platelets using Raman spectroscopy for early-stage diagnosis (Wang et al. 2014). With the predictive probability’s technique, they also added the Gaussian process for classification. With the expected probability, the Gaussian process demonstrated approximately 100% sensitivity. Raman tweezers spectroscopy was used by Manman et al. to examine platelets to detect AD.  Machine learning was then utilized to analyse the results (Lin et  al. 2022). For the experiments, triple transgenic rats were used. According to the study, samples with AD have a higher intensity ratio of 1127 cm−1 with 1001 cm−1 (CH or CC vibrations of proteins and lipids), and this ratio increases as the condition worsens. Similarly, AD patients had a lower intensity ratio of phenylalanine I (1604 cm−1) to amide I (1654 cm−1). The variations in amyloid precursor protein metabolism and the structural modifications to the α-helix in AD patients led to changes in intensity ratios.

10.8.2 Detection from Blood Plasma and Serum Human blood serum samples have been studied by Elena et  al. to detect AD (Ryzhikova et al. 2015). A 95% accuracy was achieved using artificial neural network analysis to distinguish the serum samples of AD patients and healthy control (HCs) with patients with different kinds of dementia. Another group used RS with multivariate analysis to conduct a study on human serum for the diagnosis of AD (Carota et al. 2022). In AD, the carotenoid bands (1154 cm−1 and 1519 cm−1) had less intensity, according to recorded Raman spectra. They noticed that the carotenoid band intensity likewise decreased with the severity of the illness. Pedro et al. used RS technology and infrared spectroscopy techniques to diagnose AD from blood plasma (Carmona et al. 2013). The reference sample used for the test was normal plasma, and the study included patients with low, moderate, and high AD. They discovered seven Raman marker bands that can be used to diagnose this disease, including the increased intensity of the 1672 cm−1 (β-sheet) band and reduced intensity of the 1658 cm−1 (α-helical polypeptide backbones) band in AD compared to normal samples. The SERS technique for the diagnosis of AD from blood and blood components was performed by various research groups. Yang et al. utilized the SERS technique to examine blood samples collected from AD patients (Yang et al. 2022). The use of blood samples reduces the complexity of collecting cerebrospinal fluid for the analysis of AD. For the fabrication of the SERS substrate, a mould consisting of silicon nanopillars was created through a maskless reactive ion etching (RIE) technique. To metallize the silicon mould, a layer of gold was applied onto the surface of the silicon nanopillars using electron beam evaporation. Furthermore, an extra layer of

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gold was added to the upper part of the silicon nanopillar substrate. The headflocked Au nanopillar SERS substrate is used for the detection of tau protein from blood plasma. Tau protein is one of the main marker proteins for AD. Cristiano et al. also conducted an experiment on samples from healthy controls and AD patients by the SERS technique (Carlomagno et al. 2020a). Ascorbic acid (591 cm−1), hypoxanthine (724 cm−1), and uric acid (634 and 1128 cm−1) all had increased Raman band intensities in AD. The main purine nucleobase found in the brain’s salvage route is hypoxanthine, which supports the function of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT) in the pathogenesis of AD. In AD, the accumulating hypoxanthine caused a decline in HPRT activity, which was also brought on by the accumulating uric acid. Another study on serum samples for the early diagnosis of AD was conducted by a group of researchers (Yu et al. 2021). The investigation was carried out using the SERS method. Uniform Ag nanoparticles coated with tannin were selected as the SERS detection probe. These nanoparticles were labelled with 4-mercaptobenzoic acid (4-MBA). Magnetic graphene oxide (Fe3O4@ GOs) served as the magnetic SERS substrate, boosting Raman signals and exhibiting effective dispersibility. The technique successfully identified the proteins known as Aβ1–42 and P-Tau-181, which are important markers of AD. Zhang et al. conducted an experiment for the detection of the AD biomarker p-tau protein from blood plasma using the calorimetric and SERS dual readout lateral flow assay technique (Zhang et  al. 2023). Here, the SERS substrate was prepared by grafting a layer of Raman molecule (4-MBA) onto a gold nanoparticle (AuNP)-coated substrate. The AuNp@4-MBA was again modified with 3G5; hence, the SERS substrate became AuNP@4-MBA-3G5. Compared to normal free 4-MBA and AuNP substrates, the signal enhancement from AuNP@4-MBA-3G5 is significantly higher. The current SERS system has a detection limit of 3.8 pg/mL, and in the case of calorimetric LFA, the detection limit was 60  pg/mL.  Ag or Au nanoparticlecoated magnetic polystyrene beads were used to prepare SERS substrates by Prucek et al. (2021). The PS composite with spiked gold nanoparticles was utilized to distinctly and accurately identify Tau protein, an indicator of Alzheimer’s disease, and Staphylococcus aureus infection in knee joint fluid (PJI). The model sample of tau protein was tested in this SERS substrate. This innovative composite successfully enabled the specific detection of these components. Elina et al. employed a SERS substrate of colloidal silver nanoparticles for the purpose of detecting and categorizing AD in comparison to healthy controls (HC) and other forms of dementia (OD) (Ryzhikova et al. 2019). Their study utilized blood serum as the subject of investigation and produced a sensitivity of 96% for distinguishing AD samples from HC and a sensitivity of 98% for effectively differentiating between AD, HC, and OD. Yang et al. introduced a SERS colloidal nanoprobe in the form of silver nanogap shells to identify Alzheimer’s disease (AD) biomarkers in human blood serum (Yang et al. 2019). Their work demonstrated the capability of these AgNGS nanoprobes to detect AD-associated biomarkers, specifically Aβ40 and Aβ42 effectively. Notably, this method showcased a detection limit of 0.25 pg/mL. Another neurodegenerative autosomal dominant disorder is Huntington’s disease. The Huntingtin disease state is caused due to the abnormal CAG expansion in

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exon 1 of the gene. Using Raman spectroscopy and SERS, Anna et al. studied the blood serum of transgenic R6/2 mice suffering from Huntington’s disease (Huefner et  al. 2020). Au nanoparticles were used in the SERS technique to enhance the Raman signals. To discriminate Huntington’s disease from healthy persons, they used the PCA-LDA statistical method. The levels of the Raman bands for uric acid (1120 cm−1) and phenylalanine (640, 996, and 1022 cm−1) fluctuate, depending on the disease state; people with Huntington’s disease will have differences in the levels of uric acid in their blood, which the SERS technique can detect. -1 (ALS) is a rare neurological disorder that damages the motor neurons found in the brain and spinal cord (Hardiman et al. 2017). Motor neurons provide voluntary muscle contractions, such as chewing, walking, and talking. Zhang et al. performed a SERS investigation using blood plasma to help diagnose ALS (Zhang et al. 2020). For the fabrication of the SERS substrate, plasma samples and Ag colloidal nano substrate were combined to create plasma-nanoparticle complexes. These compounds were created by deoxidizing silver nitrate with hydroxylamine hydrochloride to produce Ag nanoparticles. Due to the C-H bending of adenine and coenzyme in the ALS group, the observed data demonstrate greater intensity at 722 cm−1. This result is similar to the band at 739 cm−1, which has a high intensity in ALS plasma due to thymine and uracil. The intensity of the tyrosine band at 635 cm−1 was less in ALS plasma compared with the control sample. Researchers examined the blood serum samples of ALS patients by utilizing a portable optical fibre-based Raman system in combination with matrix factorization. (Alix et al. 2022). The study identified intensity fluctuations in specific regions of the Raman spectrum, including the amide I region (1650–1660 cm−1), the CH2 deformation of lipids and proteins at 1448  cm−1, the amide III region (1205–1340 cm−1), and the phenylalanine band at 999 cm−1. Parkinson’s disease (PD) is a neurodegenerative disease that causes a gradual and ongoing decline in neurological function, impacting the brain. This disorder leads to uncontrollable body movements such as tremors and stiffness. As per the histopathogenic perspective, the main cause of PD is the loss of cells in the basal ganglia, specifically in a specific area known as the substantia nigra. This cell death is considered to be the major factor contributing to the development of the disease. Additionally, there is an accumulation of a protein called α-synuclein (α-syn) in the surviving neurons. The protein α-syn interferes with vesicle secretion and trafficking inside the brain, thereby playing a major role in the onset and advancement of PD (Murphy et al. 2000). α-Syn has a tendency to aggregate, and it can propagate from one cell to another, similar to the mechanism seen in prion diseases. These aggregated forms of α-synuclein are observable in structures known as Lewy bodies, which are found within brain tissue.

10.8.3 Detection from Extracellular Vesicles Alice et al. investigated extracellular vesicles derived from blood samples to investigate PD. This research aimed to better understand the classification and diagnosis

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of Parkinson’s disease through the analysis of these vesicles (Gualerzi et al. 2019). In the healthy samples, there was a noticeable rise in intensity observed in the Raman band related to amide I at 1655 cm−1 and the lipid bands within the range of 2800–3000 cm−1. On the other hand, in Parkinson’s disease, the carbohydrate bands at 930, 996, 1370, and 1463  cm−1, as well as the lipid band at 1057  cm−1, show increased intensity. Carlo et al. performed Raman spectroscopy experiments on extracellular vesicles for the diagnostic purpose of sporadic amyotrophic lateral sclerosis (SALS) (Morasso et al. 2020). The researchers investigated both small and large EVs, as well as blood plasma, in the study. The large extracellular vesicles of SALS have higher lipid contents compared to healthy controls, which is evident from the increased intensity of Raman bands at 1063, 1298, and 1437 cm−1. Similarly, the intensity of the aromatic amino acid phenylalanine peaks at 621, 1002, and 1604 cm−1 decreased in SALS. Raman spectroscopy of large extracellular vesicles is a promising biomarker for SALS.

10.8.4 Detection from Tears Tears are a readily accessible bodily fluid that can be utilized to investigate different disorders. The analysis of tear samples is essential for disease diagnosis due to the noninvasive nature of the collection procedure. In this regard, SERS has been employed as a diagnostic tool for AD and moderate cognitive impairment (MCI) based on human tear samples (Cennamo et al. 2020). The technique increased the sensitivity of the fluid spectroscopy analysis, and the enhancement factor of its SERS capabilities was evaluated using aqueous solutions of rhodamine 6G on analysed tear samples using a substrate based on gold nanoparticles. The SERS substrate was created by applying a layer of gold nanoparticles on a standard microscope glass slide. Comparing individuals with MCI to those with AD and healthy controls, MCI patients exhibited reduced intensity in the Raman bands of amide I (1244–1350 cm−1). Diletta et al. conducted an investigation involving tear samples from both ALS patients and healthy controls using Raman spectroscopy and IR spectroscopy (Ami et  al. 2021). In comparison to healthy controls, tears from patients with ALS exhibit significant variations in both protein content and structure. Specifically, the ratio of the intensity of CH2 bands to CH3 bands is higher in ALS tears, indicating changes in the physicochemical properties of lipids. This finding aligns with the well-known association between ALS and dyslipidaemia, a condition characterized by abnormal lipid levels. Additionally, the study reveals a decrease in the quantity of phenylalanine in ALS tears, which suggests a potential issue with amino acid metabolism in these patients. These findings highlight the significance of tear analysis in comprehending the molecular alterations linked to ALS.  Figure  10.5a provides the Raman spectra of the tear samples from ALS patients and HCs. Figure 10.5b provides the difference in Raman spectra of ALS patients and HCs. The major intensity differences were observed at 1001, 1010, 1455, 1606, 1670, and 1770 cm−1.

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Fig. 10.6 (a) ALS, PD, AD, and control salivary Raman spectra. (b) PCA plot (Carlomagno et al. 2020b)

10.8.5 Detection from Saliva In their research, Carlomagno et  al. employed SERS to detect ALS from saliva samples (Carlomagno et  al. 2020b). To assess the SERS signal, the interactions between filtered saliva and two distinct metallic nanoparticles, specifically AgNPs and AuNPs, were examined. The outcomes were compared to those obtained from SERS based on an aluminium substrate, and it was found that aluminium foil was the most suitable substrate for the experiment. The study revealed distinctive differences in saliva between ALS patients and those with PD and AD. Specifically, the concentrations of certain lipids, such as phospholipids (at 833, 1251, and 1470 cm−1), cholesterol (at 430 cm−1), and phosphatidylinositol (at 500 and 576 cm−1), varied significantly between ALS patients and the other disease groups. The results suggest that SERS analysis of saliva can be an important diagnostic tool for ALS.  The Raman spectra and PCA plot of saliva taken from healthy individuals, PD patients, and AD patients are shown in Fig. 10.6. The SERS technique can also be used for the diagnosis of Parkinson’s disease from saliva (Carlomagno et al. 2021). Saliva samples were collected on aluminium

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foil for conducting SERS measurements. In addition to the spectroscopy analysis, statistical tools were utilized to enhance the classification of the obtained results. This study successfully demonstrated that Raman spectroscopy of saliva can lead to improved classification of Parkinson’s disease from healthy control samples. The sensitivity, specificity, and accuracy of the results are reported as 90%, 94%, and 89%, respectively. The investigation suggests that saliva-based Raman spectroscopy holds great promise as a highly accurate method for diagnosing Parkinson’s disease. In comparison to AD, distinct differences were seen in the intensity of Raman bands corresponding to individual amino acids, particularly at 643, 750, 1001, and 1580 cm−1, which are significantly altered in PD. Furthermore, changes were noted in the peaks at 770  cm−1 (associated with phosphatidylinositol) and 1540  cm−1 (related to amide II) in the Raman spectra. These distinct changes in the Raman bands indicate differences in the molecular composition and structure of single amino acids, suggesting their potential as diagnostic markers for differentiating PD, AD, and other conditions.

10.8.6 Detection from Cerebrospinal Fluids (CSF) Cerebrospinal fluid (CSF) was investigated for the diagnosis of AD using the RS technique in combination with a machine learning method (Ryzhikova et al. 2021). The pathological process of the disease primarily takes place in the cerebrospinal fluid (CSF), which has a direct link with the brain. Consequently, conducting research on CSF fluids will provide more accurate and detailed information about Alzheimer’s disease (AD). Elina and the team performed an experiment involving Raman spectroscopy and machine learning on the cerebrospinal fluid of AD patients. They discovered that the Raman band at 1045 cm−1 displayed a more pronounced signal in AD cases, which was attributed to an elevation in glycine and proline levels originating from the tau protein. Similarly, the band at 1065 cm−1 showed reduced intensity in AD, which aligned with the decline in arginine contribution caused by the tau protein and the decrease in histidine and valine contribution caused by Aβ42. These findings highlight the potential of RS in detecting specific molecular changes associated with AD in cerebrospinal fluid samples. Machine learning-based analysis also gave 84% accuracy in diagnosing the disease.

10.8.7 Detection from Fibroblasts Dimitrios et  al. conducted research on diagnosing Huntington’s disease from the skin (fibroblasts) using Raman spectroscopy (Tsikritsis et al. 2016). Patients with Huntington’s illness have higher levels of beta-sheet protein, as shown by the strong Raman band at 1220  cm−1. This is due to the protein aggregation caused by the huntingtin gene mutation. In Huntington’s illness, the lipid Raman bands at 717–719  cm−1, 1302  cm−1, and 1437–1451  cm−1 are less intense. The significant decline in cholesterol markedly distinguishes Huntington’s illness from normal

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conditions. Cholesterol is represented by several Raman bands, such as those at 608, 702, 957–960, 1440, 1444, 1659, and 1669 cm−1. To differentiate peripheral cells that are affected by Huntington’s disease, Raman spectroscopy and the partial least square approach were coupled (Muratore 2013). The dysregulation of cellular elements that are a part of the lipid raft in the plasma membrane subdomain has been connected by the Huntingtin protein in peripheral fibroblasts. Huntington’s disease can be accurately diagnosed by looking at research on the plasma membrane of easily accessible peripheral cells. Huntington’s disease altered certain Raman bands in samples compared to the control sample. In control fibroblasts, there were higher intensities in the peak area from 428 to 701 cm−1, as well as the triglyceride band at 1073 cm−1 and the fatty acid band at 1130 cm−1. The intensity of the phospholipid band at 1331 cm−1 is absent in Huntington’s disease membranes and is higher in control membranes, which indicates that Huntington’s disease membranes have phospholipid dysregulation.

10.9 Raman Spectroscopy for Tissue-Based Investigations Raman spectroscopy is widely recognized as a viable spectroscopic tool that can facilitate vital information regarding the molecular composition, biochemical modification, and interactions of tissue samples (Movasaghi et al. 2007). The difference in the molecular composition among various tissues can be realized from the Raman spectral data, and those specific spectral features can be explored for identifying tissues. Clinical diagnostic tools for tissue investigations can be realized by evaluating the Raman spectral changes in accordance with the pathological changes in molecular composition. Raman spectroscopic investigation of brain tumours was initiated in 1994 by Mizuno et al., where NIR FT Raman spectroscopy was employed to investigate the spectral features of brain tissues, including tumours. The spectral features attributed to phospholipids at 1065, 1080 and 1300 cm−1 were found to be high in the white matter. An intense band found at 1245 cm−1 in the glioma grade III tissue was indicative of the transformation of some of the 〈-helix structure into a random coil structure. Raman spectra collected with neurocytoma exhibited a Raman peak at 960 cm−1, indicating calcification of the choroid plexus. The characteristic Raman bands of carotenoids were found in the spectra of acoustic neuroma tumour samples, which were not expected to be present in normal brain tissue (Mizuno et al. 1994). Koljenović et  al. investigated the potential of RS to distinguish within vital tumour tissue and necrosis based on their biochemical distinctions to develop an in vivo Raman approach that would serve as a crucial helping hand for intraoperative brain biopsy guidance (Koljenović et al. 2002). Raman spectra collected from necrotic glioblastoma sections showed relatively increased carotenoid signal contributions (1523 and 1159  cm−1). Necrotic regions of glioblastoma also showed a strong band at 958 cm−1 that was linked to calcification, which appears helpful in identifying necrosis inside glioblastoma. In addition, Raman spectra also revealed the presence of areas with extremely high glycogen contents in tissues from a

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limited sample size. Even though the study was performed with a limited sample size, 100% accuracy was obtained using the LDA prediction model. In a recent study, RS was used to estimate the water fraction in brain tissue by employing the partial least square model generated using the spectral information obtained in the 2600–3800-cm−1 region. The bands assigned to water at 3250, 3450, and 3600 cm−1 were absent in the freeze-dried tissue samples. Krafft et al. performed a detailed Raman investigation of 12 lipids to identify the band locations associated with particular functional groups, which might be helpful to understand further the spectral characteristics of tissues and cells (Krafft et al. 2005). Koljenović et  al. investigated the importance of utilizing RS to differentiate between meningioma and dura. The findings of this study, conducted with a limited sample size, indicate that meningiomas and dura can be identified based on their spectral features. The tissue classification model created in this in vitro investigation was 100% accurate. When comparing meningioma tissues to the dura, the Raman spectra exhibit notable differences attributed to the higher content of collagen in the dura and the increased content of lipids in tumours. Using the LDA of Raman spectra, a classification model achieved a remarkable accuracy of 100% in distinguishing between dura and tumour tissue. Meningioma tissues, on the other hand, have much higher lipid content than dura (Koljenović et al. 2005). Beljebbar et  al. demonstrated Raman investigations for glioblastoma tumour development by employing a portable Raman spectrometer combined with a microprobe comprised of a core excitation fibre (400 ⎧m diameter) that was surrounded by nine collection fibres (200 ⎧m diameter), which collect the Raman scattered radiation and send it to the spectrometer (Beljebbar et al. 2010). The research encompassed both ex vivo and in vivo experiments involving the implantation of C6 cells into rat brains. The study successfully showcased the technique’s potential to distinguish between different white matter and grey matter, invasion zone, and tumours tissue, demonstrating its feasibility and efficacy. The grey matter spectrum showed high spectral contributions of proteins in comparison with white matter, whereas the spectral contributions of lipids were the opposite. It was found that variations in nucleic acid and lipid contents can be employed as spectroscopic markers for tumour development. Kalkanis et  al. used RS to generate a library of Raman spectra from healthy brains, glioblastoma multiforme (GBM), and necrosis, as well as a system for identifying these diseases (Kalkanis et al. 2014). GBM, necrosis, and surrounding normal brain tissue boundaries may be distinguished using a chosen set of critical Raman peaks that convey particular biological information (rather than compressed data). Spectral identification will be performed using discriminant function analysis (DFA), a supervised classification approach, to enable the model to be interpreted in a way that is relevant to biology. Raman spectroscopic investigations were performed on frozen tissue from GBM resections that had been banked. Using a 785 nm light source, 95 areas from 40 frozen tissue sections were measured using RS. Necrosis indicated higher protein and nucleic acid contents (1003, 1206, 1239, 1255–1266, and 1552 cm−1), although grey matter had a higher lipid content (1061, 1081 cm−1). Between these two extremes, GBM was located.

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In another important work, Jermyn et al. demonstrated that grade 2–4 gliomas can be classified sensitively, specifically via in vivo Raman spectroscopy. This is accomplished by utilizing a portable fibre optic probe approach with a compact footprint that is intended for quick intraoperative Raman scattering measurements. The resulting spectra, acquired from a tissue surface width of 0.5 mm and a depth of no more than 1 mm, contain biological data related to a wide variety of molecular components (Jermyn et al. 2015). With its compact size and real-time functionality, the handheld Raman probe is practical for brain cancer removal with little interference with the neurosurgical process. As a result, the probe can be used during the surgical process, since it can quickly identify cancer at a point of interest without the requirement for a sample or a frozen neuropathology assessment, which can interrupt the surgical workflow while done repeatedly throughout a procedure. Since the Raman technique does not demand any exogenous chemicals to induce optical contrast, it is easier to use in clinical settings. The advantage of this procedure is that it can detect cancer in a surgeon’s specific area of interest quickly, particularly in diseased white matter tracts. The system developed by Jermyn et  al. demonstrated an accuracy of 92% for separating cancerous tissue from healthy brain tissue while performing in  vivo studies with 17 glioma patients. In a later work, a thorough data acquisition characterization and optimization study of the developed probe was conducted to ascertain the ideal system operation parameters (Desroches et al. 2015). The researchers conducted an investigation to determine the best conditions for detecting Raman spectra in vivo. They examined the effects of different potential sources of surrounding light in a surgical environment. Their observations revealed that the light sources for the surgical microscope, both white and blue, as well as ambient fluorescent lights and regular operation room lights, had the most notable influence on the measurements when directed towards the tissue during the experiments. During spectroscopic measurements, it is necessary to turn off both the fluorescent lights and microscope light source. Nevertheless, conventional OR lights can remain illuminated until repositioned to avoid shining directly on the tissue under examination. The study achieved specificity and sensitivity rates of 84% and 89%, respectively, in distinguishing between necrosis and vital tissue (comprising both cancerous and normal) categories. This was accomplished using the boosted trees algorithm and a leave-one-out cross-validation strategy. In 2017, the same group introduced another interesting optical probe with various modalities that can detect diffuse reflectance spectroscopy (DRS), intrinsic fluorescence spectroscopy (IFS), and RS for increased classification accuracy (Jermyn et al. 2017). Cancer tissues were shown to exhibit greater DNA and RNA content peaks in particular, which is probably due to the increase in chromatin density. The basic building blocks of cell membranes and intracellular organelles, phospholipids and lipids, are more prevalent in malignancies than in normal tissues due to the greater cell density in tumours. The accuracy, sensitivity, and specificity of this optical multimodality were shown to be 97%, 100%, and 93%, respectively, for the identification of skin, lung, colon, and brain tumours in situ during surgery. Biomedical researchers have mostly preferred the spectral region comprising 400 and 2000 cm−1, termed the “fingerprint region for biological samples” since it

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contains a wealth of spectroscopic information. The fact that there is significant Raman scattering in the optical fibre itself in the 400–2000  cm−1 spectral range complicates the in  vivo clinical execution of this vibrational spectroscopic tool. Recording Raman spectra in the high-wavenumber (HWVN) zone (2000–4000 cm–1) can address the challenge of designing and constructing appropriate fibre-optic probes. In the study, grey matter Raman spectra exhibited higher contributions from protein, DNA, and phosphatidylcholine than white matter. Grey matter consists of neuronal cell bodies, and white matter spectra showed predominant characteristics of lipids such as cholesterol, sphingomyelin, and galactocerebroside, which can be attributed to the presence of axon bundles covered in a coating of lipoprotein myelin in white matter (Koljenović et al. 2007). To evaluate the applicability of HWN RS in distinguishing healthy brain tissue and cancerous tissue, a clinical investigation was carried out in patients with grade 2–4 glioma (Desroches et al. 2018). Asymmetric and symmetric CH2 stretches of lipids and proteins (2845–2885 cm−1), symmetric CH3 stretches arising from proteins (2930 cm−1), and OH stretching due to water molecules (at 3450 cm−1) are the main causes of the identified conspicuous peaks. Dense cancer tissue showed intense peaks (2930 cm−1) that were mostly connected with the presence of proteins. The proportion of proteins to lipids can be assessed by examining the ratio of spectral bands found at 2930 and 2845 cm−1. This measurement is particularly useful for investigating dense cancerous tissues, because research has indicated that the protein/lipid ratio tends to be higher in dense cancer tissue compared to healthy brain samples. The protein/lipid ratio in the invaded samples, however, was not significantly different from that in the normal brain. Desroches et al. demonstrated another promising modality that incorporates RS with a commercial brain biopsy needle for smooth incorporation into the operating workflow (Desroches et al. 2019). The gadget is made up of 12 collection fibres surrounding a centre lighting fibre with a core diameter of 100 ⎧m. All these fibres are silicon (cladding and core) low-OH step-index optical fibres with a numerical aperture of 0.22, which facilitates efficient Raman measurements in high-wavenumber and fingerprint (800–1600  cm−1) ranges. In this study, the mandarin of a biopsy needle was replaced with an EmVision LLC probe, which closely resembled the setup used in a previous work by Jermyn et al. in 2015. However, the differences between the two setups were related to the miniaturization and the angle-facing signal collection. Researchers have also verified the possibility of resonance Raman spectroscopy in discriminating normal meningeal brain tissues from five kinds of brain tumours comprising benign meningioma, stage III (benign), malignant meningioma, stage III (cancer), benign meningioma, stage IV (cancer), benign acoustic neuroma, and benign pituitary adenoma. The spectra of grade III malignant meningioma tumour tissue displayed an increase in the peaks at 1088 and 1302 cm−1, which shows the spectra of proteins (amides) and type I and type IV collagen. A rise in the ratio of Raman bands at 1587 and 1605 cm−1 was experimentally observed from the Raman spectrum of cancer tissue compared with both benign and normal tissue. The cancer cells that are responsible for the mitochondrial mutation in the cancer tissue result

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in the release of cytochrome c from the mitochondrial membrane, which is suggested to be the reason for the enhancement of the former peak at 1587  cm−1. Considering the intensity ratio of peaks respective to the symmetric stretching of methyl (2935  cm−1) to methylene (2880  cm−1) groups in the higher wavenumber region, malignant meningioma meningeal tissue showed a lower order coefficient than normal meningeal brain tissue. This has been justified by the presence of a more stable metabolism and biochemistry present in normal cells (Zhou et al. 2012). Label-free imaging, such as CARS and SRS approaches, is becoming more popular in the medical imaging community due to its capacity to overcome the limitations of dye-based techniques, such as heterogeneous delivery and nonspecific staining. DePaoli et  al. reported a proof-of-concept work demonstrating the first fibre-based CARS sensing of primate brain tissue. The system employed conventional silica-based fibre optics and a wavelength-tuneable fibre laser for probe development. Compared with grey matter, a prominent peak at 2845 cm−1 occurs solely in white matter; this peak is attributed to CH2 bonds, which are substantially more common in white matter myelinated fibres (DePaoli et  al. 2018). In recent work, Soltani et al. introduced a stimulated Raman scattering-spectroscopic optical coherence tomography modality that can discriminate between healthy brain tissue and brain tumour tissues. The experiments used tumour areas from the 9L gliosarcoma rat model, which mimics high-grade human gliomas. The idea was to gather information from the high wavenumber region, which carries peaks at 2947 cm−1 and 2861 cm−1 representing proteins and lipids, respectively, via Raman spectroscopy. This can provide an overview of the protein and lipid contents in different kinds of tissues, thereby helping in detecting tumorous tissue. Tumour tissues are expected to be protein-rich. Combining OCT with the stimulated Raman technique allows us to gather additional information regarding the spatially and spectrally resolved details of linear scattering structures along with the molecular spectral features of tissue (Soltani et al. 2021). Ji and colleagues demonstrated the capability of two-colour SRS microscopy in distinguishing hypercellular tumour areas from normal regions. The tumour-infiltrated areas in mouse samples were recognizable from the high-intensity ratio for 2930/2845 peaks in SRS, which arise due to densely packed cells. SRS offers significant advantages over conventional clinically accessible dye-based techniques that separate tumour-infiltrated tissues from normal brain tissue. The extravasation of intravenously injected dyes into a tumour is the foundation of dye-based methods. The inhomogeneous dye distribution within tumours has, however, long been understood. Additionally, low-grade gliomas and several other neoplastic tissues with an intact blood-brain barrier absorb little circulating dye and are challenging to photograph. SRS does not rely on the administration of dye for tumour delineation, because it examines molecular species that are present in both tissues with and without tumour infiltration at various quantities. Consequently, SRS microscopy is especially well adapted for imaging normal tissue, unlike dye-based techniques for tumour delineation (Ji et al. 2013). Kircher et al. presented a triple-modality technique incorporating MRI, photoacoustic imaging, and Raman imaging in mice with glioblastoma. Magnetic resonance imaging-photoacoustic imaging-Raman imaging nanoparticles (MPR

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nanoparticles) are administered intravenously to an animal with an orthotopic brain tumour. A 60-nm gold core wrapped with the Raman molecular marker trans1,2-bis(4-pyridyl)-ethylene makes up the MPR nanoparticle. The Raman activity occurs in the outer layer, which is a thin layer protected by a 30-nm silica covering. The particles were then modified using a maleimide linkage and 1,4,7,10-­tetraazac yclododecane-­1,4,7,10-­tetraacetic acid (DOTA)-Gd3+. As a result, a Gd3+ ion– coated gold–silica–based SERS nanoparticle (MPR) was created. The blood-brain barrier is broken, allowing the nanoparticles to cross through and finally assemble at the tumour location. The MPRs, however, cannot be identified in a healthy brain because of their inability to penetrate the blood–brain barrier due to their size. Only one injection is necessary to retain the probing agents in the tumour, and probebased identification is still achievable days after surgery. Utilizing its resolution and tissue penetration capabilities, photoacoustic imaging can guide surgeons during intraoperative bulk tumour removal. In addition, the evaluation of tissue ex vivo to ensure clear tumour margins can be performed using a Raman probe (Kircher et al. 2012). Karabeber et al. conducted a study on SERS imaging of brain tumour resection. They also demonstrated real-time SERS nanoparticle detection using a handheld Raman spectrometer. Glioblastoma multiforme (GBM) causing malignant brain tumours were removed via image-guided surgery using Au-silica SERS nanoparticles and a portable Raman scanner. The two techniques worked well together, and a comparison to histopathology revealed that using SERS nanoparticles can be a feasible approach to depict tumours. Moreover, the information obtained through the handheld Raman probe, utilizing SERS nanoparticles, uncovered additional microscopic cancer foci. Moreover, image-guided resection using SERS exhibited better results than that utilizing only white light visualization (Karabeber et al. 2014). Yue et al. developed nanoprobes capable of targeting the epidermal growth factor receptor to guide glioblastoma surgery. They utilize these nanoprobes to identify tumour boundaries preoperatively through MRI and then guide surgical resection using surface-enhanced resonance Raman scattering (SERRS) imaging (Yue et al. 2017). The research team has developed a new multimodal MR/SERRS sensor capable of identifying glioma margins by detecting the acidic microenvironment of the tumour. In the study, the physiological acidic nature of the tumour facilitates the assembly of nanoparticles, leading to the formation of 3D spherical nanoclusters that enhance both MR and Raman signals. A pair of Au nanoprobes that can rupture the blood-brain barrier and reach a brain tumour has been created. Through the formation of 3D spherical nanoclusters with notable MR and SERRS signal increases, physiological acidity initiates the nanoparticle assembly (Gao et  al. 2017). The research group addressed the limitations of their previous studies, which were conducted in isolated mouse brains, by demonstrating the effectiveness of SERRS-guided glioma surgery in a live animal model. They achieved this by administering gold nanostar-based SERRS probes intravenously (I.V.) and observing their accumulation in glioma margins in live mouse models. In this probe, gold nanostar surfaces were covalently functionalized with molecular reporters with absorption maxima in the near-infrared region. The glioma margins were identified using NIRSERRS imaging (Han et al. 2019). The details of SERS-based studies reported in neurological disorders are compiled and provided in Table 10.1.

10  Raman Spectroscopy for Detecting Neurological Disorders: Progress and Prospects 243 Table 10.1  SERS-based investigations in the area of neurological disorders Sl. no. Technique 1 SERS (silicon nanopillars) 2 SERS

Sample Blood plasma Blood serum

Neurological disorder Alzheimer’s disease Alzheimer’s disease

Marker protein/ Raman bands Tau protein Ascorbic acid (591 cm−1), hypoxanthine (724 cm−1), and uric acid (634 and 1128 cm−1) Aβ1–42 and P-Tau-181

References Yang et al. (2022) Carlomagno et al. (2020a)

SERS (Ag nanoparticles coated with tannin) SERS (gold nanoparticle, 4MBA, 3G5) SERS (Au or Ag nanoparticle coated magnetic polystyrene bead) SERS (colloidal Ag nanoparticles) SERS (Ag nanogap shell) SERS

Blood serum

Alzheimer’s disease

Blood plasma

Alzheimer’s disease

P-tau protein

Zhang et al. (2023)

Commercially purchased protein

Alzheimer’s disease

Tau protein

Prucek et al. (2021)

Blood serum

Alzheimer’s disease

Blood serum

Alzheimer’s disease Huntington’s disease

9

SERS (Ag colloid)

Blood plasma

Amyotrophic lateral sclerosis

10

SERS (gold nanoparticle)

Tear

Alzheimer’s disease and moderate cognitive impairment

3

4

5

6

7 8

Blood serum of transgenic R6/2 mice

Yu et al. (2021)

Ryzhikova et al. (2019) Aβ-40 and Aβ-42 Uric acid (1120 cm−1) and phenylalanine (640, 996, and 1022 cm−1) C-H bending of adenine (722 cm−1, thymine and uracil (739 cm−1), tyrosine (635 cm−1) Amide I (1244–1350 cm−1)

Yang et al. (2019) Huefner et al. (2020)

Zhang et al. (2020)

Cennamo et al. (2020)

(continued)

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Table 10.1 (continued) Neurological disorder Amyotrophic lateral sclerosis

Marker protein/ Raman bands Phospholipids (at 833, 1251, and 1470 cm−1), cholesterol (at 430 cm−1), and phosphatidylinositol (at 500 and 576 cm−1) Amino acids (643, 750, 1001, and 1580 cm−1), phosphatidylinositol (770 cm−1) amide II (1540 cm−1)

Sl. no. Technique 11 SERS

Sample Saliva

12

SERS

Saliva

Parkinson’s disease

13

SERS (Au- silica nanoparticle)

Brain tumour (Glioblastoma)

Karabeber et al. (2014)

14

Multimodal MR/SERRS MR/SERRS (Au nanostar)

Genetically engineered GBM mouse model Glioblastoma cell lines Mice modal

Glioblastoma

Yue et al. (2017) Gao et al. (2017)

15

Glioma

References Carlomagno et al. (2020b)

Carlomagno et al. (2021)

10.10 Conclusions Analysis of human body fluids and tissues with conventional Raman scattering is not a highly reliable alternative because of the signal’s inherent weakness, lengthy acquisition durations, interference from a strong fluorescence background, and time-consuming data processing. Researchers are diligently working to develop various types of SERS, RRS, and SRS probes that may significantly amplify the Raman signal in an effort to alleviate this issues. This area has greatly benefited from the advancements in the in vivo imaging modalities and various nanoparticle/ nano substrate synthesis techniques. SERS substrate reproducibility is a constant concern, which is a significant barrier to using it to diagnose diseases from bodily fluids. The enormous laser system required for SRS to generate pulses with high peak power is a significant obstacle to overcome in order to be applied in clinical applications despite its enormous potential for label-free sensing and imaging. The initial cost to set up a sensitive Raman system for diagnostic purposes may be significant given the cost of the laser, microscope, and a highly sensitive detector, even though Raman technology can be reagent-free. Efforts should be made to create inexpensive, miniature laser sources and detectors without significantly lowering the performance and sensitivity of the system. Active research initiatives combining spectroscopists, clinicians, data scientists, and biomedical engineers are a crucial

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necessity to make Raman spectroscopy a reliable technique for routine clinical applications.

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Cialla-May D, Krafft C, Rösch P, Deckert-Gaudig T, Frosch T, Jahn IJ, Pahlow S, Stiebing C, Meyer-Zedler T, Bocklitz T (2021) Raman spectroscopy and imaging in bioanalytics. Anal Chem 94(1):86–119 Cong S, Liu X, Jiang Y, Zhang W, Zhao Z (2020) Surface enhanced Raman scattering revealed by interfacial charge-transfer transitions. Innovation 1(3):100051 Czernuszewicz RS, Zaczek MB (2008) Resonance Raman spectroscopy. Encycl Inorg Bioinorg Chem Demirtaş Ö, Doğanay D, Öztürk İM, Ünalan HE, Bek A (2020) Facile preparation of nanoparticle based SERS substrates for trace molecule detection. Phys Chem Chem Phys 22(37):21139–21146 DePaoli DT, Lapointe N, Messaddeq Y, Parent M, Côté DC (2018) Intact primate brain tissue identification using a completely fibred coherent Raman spectroscopy system. Neurophotonics 5(3):035005 DePaoli D, Lemoine É, Ember K, Parent M, Prud’homme M, Cantin L, Petrecca K, Leblond F, Côté DC (2020) Rise of Raman spectroscopy in neurosurgery: a review. J Biomed Opt 25(5):050901 Desroches J, Jermyn M, Mok K, Lemieux-Leduc C, Mercier J, St-Arnaud K, Urmey K, Guiot M-C, Marple E, Petrecca K (2015) Characterization of a Raman spectroscopy probe system for intraoperative brain tissue classification. Biomed Opt Express 6(7):2380–2397 Desroches J, Jermyn M, Pinto M, Picot F, Tremblay M-A, Obaid S, Marple E, Urmey K, Trudel D, Soulez G (2018) A new method using Raman spectroscopy for in vivo targeted brain cancer tissue biopsy. Sci Rep 8(1):1792 Desroches J, Lemoine É, Pinto M, Marple E, Urmey K, Diaz R, Guiot MC, Wilson BC, Petrecca K, Leblond F (2019) Development and first in-human use of a Raman spectroscopy guidance system integrated with a brain biopsy needle. J Biophotonics 12(3):e201800396 Ding S-Y, You E-M, Tian Z-Q, Moskovits M (2017) Electromagnetic theories of surface-enhanced Raman spectroscopy. Chem Soc Rev 46(13):4042–4076 Doruyter AG, Parkes J, Carr J, Warwick JM (2021) PET-CT in brain disorders: the South African context. SA J Radiol 25(1):2201 DPHHS M (n.d.) Neurological disorders. montana.gov. https://dphhs.mt.gov/schoolhealth/ chronichealth/neurologicaldisorders Fazal FM, Block SM (2011) Optical tweezers study life under tension. Nat Photonics 5(6):318–321 Gao X, Yue Q, Liu Z, Ke M, Zhou X, Li S, Zhang J, Zhang R, Chen L, Mao Y (2017) Guiding brain-tumor surgery via blood–brain-barrier-permeable gold nanoprobes with acid-triggered MRI/SERRS signals. Adv Mater 29(21):1603917 Gautam A et al (2022) Towards modern-age advanced sensors for the management of neurodegenerative disorders: current status, challenges and prospects. ECS Sensor Plus 1:042401 González-Domínguez JM, Colusso A, Litti L, Ostric A, Meneghetti M, Da Ros T (2019) Thiolated graphene oxide nanoribbons as templates for anchoring gold nanoparticles: two-dimensional nanostructures for SERS. ChemPlusChem 84(7):862–871 Gowert NS, Donner L, Chatterjee M, Eisele YS, Towhid ST, Münzer P, Walker B, Ogorek I, Borst O, Grandoch M (2014) Blood platelets in the progression of Alzheimer’s disease. PLoS One 9(2):e90523 Gualerzi A, Picciolini S, Carlomagno C, Terenzi F, Ramat S, Sorbi S, Bedoni M (2019) Raman profiling of circulating extracellular vesicles for the stratification of Parkinson’s patients. Nanomedicine 22:102097 Han L, Duan W, Li X, Wang C, Jin Z, Zhai Y, Cao C, Chen L, Xu W, Liu Y (2019) Surfaceenhanced resonance Raman scattering-guided brain tumor surgery showing prognostic benefit in rat models. ACS Appl Mater Interfaces 11(17):15241–15250 Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, Shaw PJ, Simmons Z, Van Den Berg LH (2017) Amyotrophic lateral sclerosis. Nat Rev Dis Primers 3(1):1–19 Harper LC 2020 Alzheimer’s association facts and figures He Z, Rong T, Li Y, Ma J, Li Q, Wu F, Wang Y, Wang F (2022) Two-dimensional TiVC solidsolution MXene as surface-enhanced Raman scattering substrate. ACS Nano 16(3):4072–4083

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Nanotools for Screening Neurodegenerative Diseases

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Bakr Ahmed Taha, Mohd Hadri Hafiz Mokhtar, Retna Apsari, Adawiya J. Haider, Rishi Kumar Talreja, Vishal Chaudhary, and Norhana Arsad

Abstract

This paper underlines the critical need for novel diagnostic techniques against the increasing worldwide burden of neurodegenerative disorders (NDDs). The intricacies of Alzheimer’s, Parkinson’s, and Huntington’s necessitate very accurate and sensitive early detection strategies. In addition, it provides an essential look at the promise of the role of nanotechnology and the potential for nanoscale material and technology integration to revolutionize preclinical disease diagnostics. Furthermore, it allows for the pinpoint identification of biomarkers and pathological alterations. We discussed different types of nanotools, including nanoparticles, nanosensors, imaging agents, and nanomedicine. This process of B. A. Taha · M. H. H. Mokhtar · N. Arsad (*) Photonic Technology Laboratory, Department of Electrical, Electronic and Systems Engineering, Faculty of Engineering and Built Environment, Universiti Kebangsaan Malaysia, UKM, Bangi, Malaysia e-mail: [email protected]; [email protected] R. Apsari Department of Physics, Faculty of Science and Technology and Department of Engineering, Faculty of Advanced Technology and Multidiscipline, Universitas Airlangga, Jl. Mulyorejo, Surabaya, Indonesia e-mail: [email protected] A. J. Haider Applied Sciences Department/Laser Science and Technology Branch, University of Technology, Baghdad, Iraq R. K. Talreja Vardhman Mahavir Medical College and Safdurjung Hospital, New Delhi, India V. Chaudhary Research Cell and Department of Physics, Bhagini Nivedita College, University of Delhi, New Delhi, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_11

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metamorphosis, however, has its challenges. The development of these cutting-­ edge instruments necessitates careful thought on issues of ethics, safety, and biocompatibility. Despite these limitations, nanotools’ importance in changing the course of neurodegenerative disease screening is undeniable. Keywords

Nanotools · Neurodegenerative diseases · Early detection · Nanotechnology · Biomarkers

11.1 Introduction Early identification and screening for neurodegenerative illnesses are essential to enhance clinical diagnosis, create more effective therapies, and improve patient’s quality of life. The ability to identify neurological biomarkers in blood has revolutionized the diagnosis and prognosis of neurodegenerative diseases due to recent technical breakthroughs (Kumar and Hassan 2021; Taha et al. 2022a, 2023a, b). It has proven that speech analysis using machine learning algorithms and signal processing techniques may detect early symptoms of diseases, even in background noise (Taha et al. 2022b, c, 2023c; Braga et al. 2018). Behavioural and cognitive traits can be measured and integrated into noninvasive systems for early identification and tracking of degenerative disorders. Late diagnoses of Alzheimer’s disease are on the rise and are associated with worse results (Mckenzie 2020). It highlights the importance of having ready access to early detection services. Novel techniques and the finding of new druggable targets are necessary because there are currently no viable disease-modifying therapies for neurodegenerative illnesses (Swalley 2020). Various domains, such as healthcare, use nanoscale materials and structures, and this innovation has transformed the medical landscape, generating advanced tools for disease screening and treatment (Anjum et al. 2021; Haider et al. 2022, 2023a). Recent attention has been to nanocarriers due to their numerous advantages in drug delivery. These encompass safeguarding drugs, extending release duration, enhancing pharmacokinetics, and directing drug distribution toward afflicted regions (Fernandes et al. 2021). Nanomaterials have applications in bioimaging, biosensing, and enzyme-based processes (Abbas et al. 2021). Notable examples, such as iron oxide nanoparticles and carbon nanotubes, exhibit promise across diverse applications. Nanopharmaceuticals, a subset of nanotechnology, enhance healthcare delivery through augmented surface area, improved solubility, and heightened oral bioavailability. The potential influence of nanotechnology is profound in the realms of healthcare service quality and medical distribution enhancement (Adeyemi et al. 2021). The research investigates how nanotechnology plays an active role in the early detection of neurodegenerative disorders, including Alzheimer’s and Parkinson’s. It demonstrates the importance of catching these conditions early so that treatment can be more effective, the underlying causes of neurodegenerative disorders, and

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the challenges of finding therapies that might stop or reverse their progression. It also emphasizes identifying neurodegenerative diseases as early as possible before noticeable cognitive or motor symptoms appear. Furthermore, nanotechnology offers possibilities for the rapid diagnosis of neurodegenerative disorders. In addition, it sheds light on where we are developing diagnostic tools powered by nanotechnology and aimed explicitly at neurodegenerative diseases (Rabanel et al. 2019). Mootaz M. Salman and colleagues explained how neurodegenerative disorders (NDs), including Alzheimer’s, Parkinson’s, ALS, and Huntington’s, may be treated using drugs created using computer-aided drug design (CADD) techniques. Millions of individuals worldwide suffer from NDs, all of which are fatal. By reducing the number of ligands that must be screened in biological tests, CADD approaches assist in lowering the cost, time, and effort necessary to create novel medications. This study updates a previous summary of treatment targets for different NDs and addresses the benefits and drawbacks of these approaches (Salman et  al. 2021). Figure 11.1 shows the nanotools used to identify neurodegenerative disorders early and nanotools subgroups for illness diagnosis.

Fig. 11.1  Categories of nanotools applied to the early detection of neurodegenerative diseases

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11.2 Role of Nanotools in Early Detection Nanotools increase the sensitivity and accuracy of disease detection due to their unique properties and capabilities. Red-shifted absorbance or conductance of nanoparticles like gold nanoparticles can be employed to detect the offending biomolecules (Fazlali et al. 2022; Chaudhary et al. 2023a, b, c). This research discusses nanodiagnostics for detecting leishmaniasis-related molecular markers and other biomarkers. It emphasizes the need for a portable, genuine, and reliable assay that can be performed in primary care settings, highlighting the limitations of current diagnostic techniques. It also highlights the benefits of nanoparticle (NP)-based biomolecular detection methods, which are quick, inexpensive, and yield fast, one-­ step, reliable findings with adequate sensitivity and specificity (Khademolqorani and Banitaba 2022; Alwazny et al. 2023; Yousif et al. 2023). Furthermore, highlighting the immense potential of nanodiagnostics in human and veterinary medicine, this article includes the most promising diagnostic techniques. The authors discuss in depth the capacity for biomolecular identification, its benefits, and its limitations. Overall, the report shows the promise of nanodiagnostics in advancing leishmaniasis detection and therapy and adds to establishing new frontiers in this area (Gedda et  al. 2021). Rapid detection of pathogen-related nucleic acids is made possible by nanoscale characteristics integrated into microsensors (Savaliya et al. 2015). Precise quantification of analytes is made possible by microdevices that employ nanocompartments (Kelley et  al. 2014). Improved illness diagnostics is another benefit of nanotechnology, which allows for the fabrication of protein or gene chips out of nanomaterials that can be incorporated into nano-fluidic devices (Mitchell and Carlson 2018). Point-of-care testing (POCT) platforms based on nanotechnologies, such as miniaturized diagnostic magnetic resonance testing and paper-based POCT testing, provide specific, sensitive, accurate, quick, low-cost, and user-­ friendly diagnostics for infectious illnesses (Wang et al. 2017). These developments in nanodiagnostics boost the sensitivity, speed, and accuracy of detection, enabling the detection of biomarkers in clinical samples that were previously undetected. The cost implications and public health issues resulting from using traditional diagnostic procedures for these disorders are substantial (Song et al. 2020). Using speech and signal processing techniques has shown promise in detecting neurodegenerative disorders, such as Parkinson’s disease using unsupervised methodologies and machine learning algorithms (Iram et al. 2015). Early identification and progression monitoring of degenerative illnesses (Mundra and Mandot 2021) are made possible by noninvasive devices that assess and combine behavioural and cognitive aspects. Patients’ lives are improved due to early diagnosis since therapies are more likely to be successful and will use fewer resources to fight the condition (Gao et al. 2019).

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11.3 Taxonomy of Nanotools for Neurodegenerative Disease Screening This section discusses the forefront of research concerning nanotools to detect neurodegenerative diseases. This dynamic field encompasses a diverse array of technologies, each of which contributes uniquely to the early identification and diagnosis of these conditions. Among the pioneering avenues of exploration are nanomedicine, Imagen agents, nanosensors, laboratory-on-a-chip devices, and nanoparticles.

11.3.1 Based on Nanomedicine Neurodegenerative illnesses like Alzheimer’s and Parkinson’s may benefit from nanomedicine’s potential in early detection and diagnosis. Effective nano-­ therapeutics that can penetrate the brain’s protective blood-brain barrier and target particular regions are now within reach (Li et al. 2021). Furthermore, research is being conducted to determine the efficiency of both standard and new medicines for treating Alzheimer’s disease (AD) by using nanomedicine-based technologies, such as cutting-edge nanoparticles (Nowacek et al. 2009). New methods for the difficulties of accessing the brain have been presented in the form of nanotechnology-based treatments for Alzheimer’s disease (AD) and Parkinson’s disease (PD) (Lima Leite 2016). When studying neurodegenerative illnesses like Alzheimer’s and Parkinson’s, nanotechnology offers novel insights into their underlying processes and pathways. In sum, nanomedicine shows promise as a novel approach to the screening, diagnosis, and treatment of neurodegenerative disorders (Hernando et al. 2017). AD biomarkers are being studied and described, both those that have been around for a while and others that are relatively new to the scene. The most promising biomarkers, including NfL, MMPs, p-tau217, YKL-40, SNAP-25, VCAM-1, and Ng/ BACE, are highlighted. Amanda Cano and colleagues are researching cutting-edge molecular techniques for treating AD and nanomedicine-based technologies that can deliver medications directly to the brain and monitor indicators of disease development (Cano et al. 2021). Nanodevices, including polymeric, lipid, and metal-based ones, are the subject of intensive research due to their potential to enhance the efficacy of established and experimental treatments for AD (see Fig. 11.2). This article updates the present state of AD, covering its prevalence, pathology, and treatment possibilities. Future possibilities for treating AD are also discussed, along with in vitro and in vivo research projects. The report stresses the importance of developing safer and more efficient drug administration methods for alleviating AD symptoms and addressing the disease’s underlying causes. The report also indicates that nanotechnology has potential as a means of delivering drugs directly to the site of action. The report also discusses using in vitro cell culture and transgenic rat models in AD research. The research adds to our knowledge of AD and its therapeutic possibilities (Tezel et al. 2019).

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Fig. 11.2  Diagnostic and therapeutic Alzheimer’s disease based on nanomedicine. (Reprinted and permission from Cano et al. 2021, Copyright 2021, Journal of Nanobiotechnology)

11.3.2 Based on Imagen Agents Neurodegenerative illnesses, such as Alzheimer’s disease (AD), may benefit from using imaging agents. The blood-brain barrier is breached, and high bioavailability at the site of action is achieved when these drugs are tailored to target specific cells or areas (Bolognesi 2017; Zhang et al. 2021). The use of nanomaterials in diagnosing and treating AD has shown promise. They can be utilized to improve the efficacy of current treatments for Alzheimer’s disease. Moreover, theranostic small molecules have evolved as a concurrent imaging technique for treating AD. These compounds combine therapeutic and imaging functions. These compounds may help accelerate the development of personalized treatments for Alzheimer’s disease. Neurodegenerative illnesses like Alzheimer’s might benefit significantly from imaging agents, especially nanomaterials and theranostic small molecules (Xu et al. 2021). This comprehensive review summarizes PD, highlighting its status as a progressive neurodegenerative disorder affecting the elderly and contributing significantly to global disability. Furthermore, it focuses on the neuropathological hallmarks of PD, including α-synuclein protein aggregates and the typical motor symptoms like tremors, rigidity, and bradykinesia. Dopaminergic therapy initially manages these symptoms effectively, but its efficacy diminishes over time. In addition, it discusses the evolving field of disease-modifying agents supported by translational molecular imaging concepts, which target α-synuclein accumulation and other pathways

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Fig. 11.3  Applying translational molecular imaging techniques in the context of medication development for Parkinson’s disease. (Reprinted and permission from Haider et  al. 2023b, Copyright 2023, Molecular Neurodegeneration)

contributing to PD.  Molecular imaging modalities such as PET and SPECT are explored for studying PD in animal models and living patients. The review also delves into peripheral biomarkers, autonomic dysfunction’s role, and the significance of α-synuclein as a potential biomarker (Haider et al. 2023b). Figure 11.3 shows PD encompasses clinical presentation, pathophysiology, and diagnostic imaging. Figure 11.3a Motor and non-motor symptoms are cardinal in PD.  Figure  11.3b Key hallmarks include α-synuclein aggregates, mitochondrial dysfunction, microglial activation, and cytokine release. Figure  11.3c Molecular imaging via PET and SPECT reveals striatal degeneration non-invasively, visualizing DAT, DDC, and VMAT2.

11.3.3 Based on Nanosensors A nanosensor is a device that detects and quantifies tiny chemical or physical characteristics. Nanotechnology, the study of and practice of working with matter at the atomic and molecular levels, is at the heart of these sensors. Due to their great sensitivity, tiny size, and potential for real-time monitoring, nanosensors have garnered substantial attention in various sectors (Huh et al. 2015).

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Nanosensors can remarkably identify biomarkers linked to neurodegenerative disorders, owing to their exceptional specificity and sensitivity. It created a diverse range of nanosensors for this specific objective. A study conducted by Fan et  al. proposes that colorimetric sensors are a viable and efficient method for detecting neurodegenerative biomarkers (Fan et al. 2021; Manea et al. 2023). These sensors provide a cost-effective and expeditious alternative approach to traditional detection techniques. Nanocarriers, including magnetic nanoparticles, carbon nanotubes, and quantum dots, have demonstrated potential in the transportation of bioactive substances for the therapeutic intervention of neurodegenerative disorders and in the detection of biomarkers (Karaboğa and Sezgintürk 2022). Murti et al. (Bilal et al. 2020) have emphasized the improved clinical application and analytical performance of various biosensors, such as electrochemical, fluorescence, plasmonic, photoelectrochemical, and field-effect transistor (FET)-based sensors, in the detection of neurodegenerative biomarkers. The detection methods based on nanopores, as described in the study by Lenhart et al. (Cano et al. 2021), present a cost-effective, efficient, and scalable way for identifying biomarkers associated with neurodegenerative diseases. In general, nanosensors offer a potentially advantageous pathway for the timely identification and assessment of neurodegenerative disorders. Kayoung Kim and colleagues highlight a significant breakthrough in (AD) diagnosis and present a pioneering approach using aligned carbon nanotubes (CNTs) to detect multiple AD biomarkers in human plasma with clinical accuracy and sensitivity. The CNT sensor array exhibits impressive precision, sensitivity, and accuracy, supported by low variation, ultralow detection limit, and high recovery rate. By analysing biomarker ratios in clinical blood samples, the sensor array effectively distinguishes AD patients from healthy individuals with high sensitivity, selectivity, and accuracy. This innovation holds great promise for transforming AD diagnostics. The CNT sensor array optimized for AD biomarkers is depicted schematically in Fig. 11.4. CNTs’ femtomolar sensitivity and excellent sensor-to-sensor consistency are made possible by their unidirectional alignment and dense design. Notably, the tightly aligned CNT sensor array accurately distinguished patients from healthy controls with an accuracy of around 88.6%.

11.3.4 Based on Lab-on-a-Chip Devices Lab-on-a-chip technologies provide a quick, easy, and inexpensive alternative method for diagnosing neurodegenerative disorders. Minimize blood samples and reagent volumes and analysis times short with the help of these devices because of the use of microfluidic technology (Akther et al. 2022). It can analyse various biomarkers in the blood to diagnose neurodegenerative disorders. Due to their portability and ease of use, lab-on-a-chip technologies may one day allow on-site patient diagnostics during urgent situations. Small biosensors are included in these devices

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Fig. 11.4  A schematic description of a compact CNT sensor array for detecting AD biomarkers

to increase detection accuracy and repeatability, enabling real-time monitoring (Song et al. 2021). In recent decades, the increasing prevalence of neurodegenerative diseases (NDDs) has spurred interest in innovative biological platforms for studying disease progression and drug efficacy. Among these, the blood-brain barrier (BBB) has been adapted into an organ-on-a-chip (OoC) model, offering insights into NDDs and facilitating drug permeability testing. A notable enhancement is the integration of real-time biomarker detection and automated drug analysis, enhancing efficiency for potential commercial use. This perspective outlines various BBB-OoC configurations and critically examines those incorporating electronic readout systems. It emphasizes the potential of biosensor integration within BBB-OoC to monitor NDD progression and drug cytotoxicity using biomarkers (Mir et al. 2022). Figure 11.5a Blood-brain-barrier-on-a-chip platform with integrated biosensors. Figure  11.5b demonstrates several ways for BBB-oC construction containing PMMA layers in stack conformation with TEER system integrated, hydrogel composed of collagen, Matrigel, and hyaluronic acid and its TEER system, PDMS layers in flank position to imitate the brain’s natural extracellular matrix, PDMS layers in flank position. Polycaprolactone/poly(d,l-lactide-co-glycolide) (PCL/PLGA)

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A

B

Fig. 11.5  Monitoring neurodegenerative diseases based on biosensor integration in a blood-brain barrier-on-chip device. (Reprinted and permission from Mir et  al. 2022, Copyright 2022, ACS sensors)

microfluidic tubular configuration was formed by freeze-coating a 3D-printed sacrificial template. Tubular structure microchannel using viscous finger patterning approach employing type I collagen hydrogel and its TEER system sequentially. Lab-on-a-chip (LOC) technology is discussed in this research to create pro-/ antiangiogenic nanomedicines for treating neurological disorders. The primary contribution of this research is a review of the potential of LOCs in the creation of nanomedicines for diseases associated with brain angiogenesis. This study discusses how LOCs may be used to simulate the brain’s micro-vasculature and the difficulties of creating consistent and repeatable settings for drug testing in the

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brain. The report also examines the possible future uses of vascularized body-on-­ chip technology for drug screening, which connects eight distinct organs, including the brain and a blood-brain barrier (Parimalam et al. 2019).

11.3.5 Based on Nanoparticles Scientists use nanoparticle power to investigate their use in specific detection and imaging. The accuracy of diagnostic methods can be improved by functionalizing nanoparticles to interact precisely with disease indicators, providing insight into the existence of neurodegenerative illnesses at an earlier stage (Ibrahem et al. 2023; Li et  al. 2016; Wei et  al. 2013; Baghayeri et  al. 2019). Researchers present a nanoparticle-­based technology for treating motor symptoms of Parkinson’s disease in a mouse model; it consists of albumin/PLGA nanosystems loaded with dopamine (ALNP-DA), which can cross the blood-brain barrier and restore dopamine levels in the nigrostriatal pathway. They are creating a noninvasive nano-therapeutic approach for PD that allows for more targeted medication administration at lower doses and across the difficult brain-blood barrier (BBB). The restoration of motor coordination, balance, and sensorimotor performance to the level seen in non-lesioned (Sham) animals demonstrates the neurotherapeutic potential of ALNP-DA in a mouse model of Parkinson’s disease. Due to their ability to penetrate the BBB and transport the target medicine to the brain, the discovery of ALNPs represents a novel and promising approach to treating Parkinson’s disease (Monge-Fuentes et al. 2021) (see Fig. 11.6). Claudia et al. discussed the current status of nanoengineered delivery systems for brain targeting in treating neurodegenerative illnesses, including Alzheimer’s, Parkinson’s, and Huntington’s. Nanotechnology provides a new avenue for developing effective and novel treatment solutions for NDs by manipulating materials on a

Fig. 11.6  The nanosystem containing dopamine/phthalocyanine and interaction with the blood-­ brain barrier system can deliver a drug or compound to a specific brain area and slowly release it over time. (Reprinted and permission from Monge-Fuentes et al. 2021, Copyright 2021, Scientific Reports)

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scale typically between 1 and 100 nm. Nanoparticles that can pass the blood-brain barrier can deliver active chemicals to specific regions in the brain, where they will have the least unwanted side effects. The report emphasizes nanoparticle-guided brain medication delivery’s therapeutic potential in neurodegenerative illnesses (Riccardi et al. 2021).

11.4 Conclusion Neurodegenerative illnesses like Alzheimer’s and Parkinson’s can be detected using nanotechnology. In addition, nanotechnology opens up exciting new avenues for developing drugs and theranostics to combat neurodegenerative conditions. Nanotechnology-based nanomedicine devices have effectively penetrated the brain’s protective barrier, opening new avenues for diagnosis and therapy. It offers high-throughput screening techniques to discover anti-aggregation chemicals for protein-conformational illnesses, such as neurodegenerative disorders. With the help of nanotools, personalized medicine as early detection, improved diagnosis, and precise treatment of neurodegenerative diseases become possible. Throughout this chapter, we’ve explored nanoparticles, nanosensors, imaging agents, and nanomedicine, all promising to reveal the first symptoms of disorders. Although this trip holds much promise, it has its share of difficulties. In conclusion, integrating nanotools, IoT, and 5G technology facilitates better screening for neurodegenerative diseases and ignites a fundamental shift in healthcare delivery. It goes beyond the limits of conventional diagnosis, heralds in a new era of preventative care, and paves the way for a future when early interventions and individualized therapies are the norm, giving people all over the world an unknown reason to have hope for a better future in terms of their health. Acknowledgements  The authors acknowledge Ministry of Higher Education (MOHE) Malaysia, Universiti Kebangsaan Malaysia, Photonic Technology Research Group, Pusat Kejuruteraan Elektronik Dan Komunikasi Terkehadapan (PAKET), Faculty of Engineering and Build Environment, Universiti Kebangsaan Malaysia and Mandat Research from Universitas Airlangga.

Funding  Research Grant Scheme (FRGS), grant number FRGS/1/2021/TK0/ UKM/02/17 funded by the Ministry of Higher Education (MOHE) Malaysia, dana pecutan and Ganjaran Penerbitan, grant number GP-K013436, Universiti Kebangsaan Malaysia and The Scheme of International Research Network (IRN), Ref. No: 1672/UN3.LPPM/PT/01.03/2023 from Universitas Airlangga, Indonesia.

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Design of Therapeutic Nanomaterials for Amelioration of Alzheimer’s Disease

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Nibedita Pradhan and Tapan Kumar Si

Abstract

Alzheimer’s disease is the most common form of progressive late-onset dementia. The prevalence of multidimensional adversity of Alzheimer’s disease imposes myriad challenges for its therapeutic development. Till now, there is no proper therapy or early-stage detection tool for this disease. Nanotechnology has revolutionized and reinforced the progress of therapeutics development for the treatment of Alzheimer’s disease. The profound application of nanotechnology improved the diagnosis as well as therapeutic approaches. It offers high-­ throughput technology for detection and monitoring of disease progression as well as promising approaches for treatment/therapy. In this chapter, the current state-of-art of nanoparticle-based therapeutics for alleviating Alzheimer’s disease will be discussed. Here, we intend to provide an overview regarding the design mechanism of action of nanotherapeutics along with the key bottleneck factors associated with their clinical availability. Keywords

Alzheimer’s disease · Nanomodulators · Phototherapy · Neuroinflammation · Biomimetic nanoparticle · Amyloid fibrillation inhibitor

N. Pradhan (*) Department of Life Sciences, Kristu Jayanti College (Autonomous), Bangalore, India T. K. Si Department of Chemistry, Bidhan Chandra College, Asansol, India © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Gautam, V. Chaudhary (eds.), Theranostic Applications of Nanotechnology in Neurological Disorders, https://doi.org/10.1007/978-981-99-9510-3_12

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12.1 Introduction Alzheimer’s is the most common form of late-onset dementia manifested by memory and cognitive decline and abnormal neuropsychiatric behaviour. According to the Alzheimer’s Association, USA, almost 47 million people are now suffering from this fatal neurodegenerative disease, and it is predicted that the number will be 76 million within the next decade (Alzheimer’s Association 2023). It is the sixth leading cause of death in the USA, and it is going to be the third major cause of death after heart disease and cancer in old Americans. According to the Alzheimer Related Disorder Society India (ARDSI) report, in 2020, an estimated 5.3 million people above the age of 60 had dementia in India. The high rate of global occurrence and the huge economic burden of treatment are two alarming concerns related to Alzheimer’s disease (AD) (Alzheimer’s Association 2023). However, according to the World Health Organization database, the estimated global prevalence of AD is approaching quadrupling in the coming decades, and approximately 114 million people will be affected by 2050 (Alzheimer’s Association Report 2015). In 1906, Alois Alzheimer first described the disease, the presence of neurofibrillary tangle and amyloid plaques, by analysing the brain tissue of a patient who died at the age of 51 from an unknown mental illness (O’Brien and Wong 2011). In spite of significant research efforts, there is no proper therapy, cure and diagnosis for AD. The lack of proper knowledge regarding the multifactorial complex molecular mechanism of onset of AD, failure of early diagnosis of disease onset and the presence of bloodbrain barrier causes the advancement of therapeutic research for AD more challenging. Alzheimer’s disease can be grouped based on the age of disease onset and cause if it’s spontaneous or specific genetic mutations are responsible. Sporadic late-onset AD is the most prevalent one, with 95–97% prevalence. The occurrence rate of early-onset familial AD (affected individuals are under 65  years of age) is near about 3–5% (Villemagne et al. 2013). The early onset familial AD, caused by hereditary mutations, represents nearly 2% of the diagnosed cases. In the case of FAD, mutations in the gene coding for amyloid precursor protein (APP; chromosome 21), presenilin 1 (PS1, chromosome 14) and presenilin 2 (PS2, chromosome 1) are considered to be associated with the production of abnormal, precisely the long form of amyloid beta peptide (amyloid beta 1–42) (Villemagne et al. 2013). In the case of sporadic AD, nearly 25% of the patient carries the e4 allele of the apolipoprotein E gene (Apo E gene, chromosome 19), though the exact mechanism of the contribution of Apo E to the increase of Aβ level is still unknown (Villemagne et al. 2013). Ageing is considered as the primary risk factor for the onset of sporadic AD. The other prominent risk factors associated with sporadic AD are diabetes, hypertension, dyslipidaemia, etc. The characteristics of the histopathology of AD are extracellular aggregates of amyloid beta plaques and intracellular neurofibrillary tangles made of hyperphosphorylated microtubule-associated tau protein. The pathophysiology of AD is associated with neuronal loss and/or deposition of amyloid plaques in specific locations of the brain, hippocampus, amygdala, entorhinal cortex and cortical association

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areas of temporal, frontal and parietal cortices, along with subcortical nuclei, e.g. serotonergic dorsal raphe, noradrenergic locus coeruleus and cholinergic basal nucleus. It has been found that there is a defined pattern of the deposition of the tangles. It initiates from the entorhinal cortex, followed by the entorhinal cortex, then the CA1 region of the hippocampus and, finally, the cortical association areas where the frontal, parietal and temporal lobes are severely damaged. In addition, the deposition of tau protein is closely associated with cognitive decline as well as hippocampal atrophy. Furthermore, with the progression of AD, there is severe loss of neurons and atrophy in the tempo frontal cortex, where deposition of amyloid plaques, clusters of abnormal protein fragments and the tangled bundle of fibres causes the accumulation of macrophages, monocytes in the cerebral cortex and triggers severe inflammation (O’Brien and Wong 2011). The disease progression can be categorized into four stages. The initial stage is mild cognitive impairment (MCI), which shows a range of symptoms that do not alter daily life significantly. Only 6–25% of the people with MCI further develop AD every year. The later stage of AD, mild and moderate AD, is characterized by significant cognitive decline and deficits in independence, which culminates in complete dependence on caregivers and, finally, severe personality deterioration (severe AD). Other symptoms associated with AD are loss of judgement, perplexity, withdrawal, irritations and hallucinations. At the initial phase, Aβ plaques develop in the basal, temporal and orbitofrontal neocortex region and with the progression of the disease, the deposition forms in the neocortex, hippocampus, amygdala, diencephalon and basal ganglia. The Aβ plaques can also be found throughout the cerebellar cortex, mesencephalon and lower brain stem at critical stage (Kidd 2008). However, the abnormal production, formation of nearly insoluble, proteaseresistant Aβ plaques and neurofibrillary tangles and deposition in brain tissue are unequivocally accepted major factors responsible for AD progression and pathogenesis (Fowler and Chiang 2014). Unfortunately, the all-inclusive molecular scenario and exact biochemical cascade responsible for the onset of AD are still unknown. A number of existing hypotheses aimed to explain the factors responsible for the origin of the onset of AD. These are amyloid cascade hypothesis, tau hypothesis, cholinergic hypothesis, mitochondrial cascade hypothesis, metabolic hypothesis, dendritic hypothesis, neuroinflammation and oxidative stress-related hypothesis. Among all these, one of the most accepted hypotheses is the amyloid cascade hypothesis.

12.2 Amyloid Cascade Hypothesis Amyloid beta is a proteolytic product of amyloid precursor protein (APP), an integral transmembrane protein found in different cell types, including neurons and glial cells. In normal physiological conditions, APP is cleaved by α-secretase to form a soluble sAPPα fragment, which remains extracellularly, and another 83-amino acid long membrane-anchored peptide. sAPPα has been shown to regulate neuronal excitability, enhance neuronal resistance towards oxidative and

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metabolic stresses and improve synaptic plasticity memory formation and learning ability. In pathological conditions, the APP is preferentially cleaved by β-secretase, leading to the formation of two fragments; one is sAPPα and another 99 amino-acid long (C99) membrane-bound fraction. Metabolism of C99 by γ-secretase produces Aβ (1–40) or Aβ (1–42) peptides, responsible for senile plaque formation (Higgins 1992; Haass et al. 2012). In contrast to neuroprotective sAPPα, Aβ peptides cause loss of synapse, reduce neuronal plasticity, induce oxidative stress, dysregulate calcium homeostasis, induce neuroinflammation, etc. (Tyler et al. 2002). The amyloid cascade hypothesis considers that the formation, aggregation and deposition of Aβ peptides, particularly Aβ (1–42), are the primary cause of neurotoxicity and neurodegeneration related to AD pathogenesis (Selkoe 2004).

12.3 Drug Development Inadequate knowledge regarding the exact molecular mechanism of multifactorial AD leads to the identification of several targets for therapeutics development like misfolded Aβ, amyloid precursor proteins, Tau, secretases, GSK3β, CDK5, etc. (Hardy and Selkoe 2002; Drachman 2014; Higuchi et al. 2005; Huang and Mucke 2012), However, only a few of these are highlighted here due to the limited scope of the present article.

12.3.1 β-Secretase Inhibitor In neuropathological condition, the β-secretase enzyme complex initially processes the amyloid precursor protein (APP) and initiates the amyloid cascade for the production of amyloid beta. It has been found that inhibition of β-secretase causes diverse side effects, as the enzyme has multiple target substrates. Few β-secretase inhibitors are under clinical trial and have shown significant reduction (80–90%) of Aβ production in cerebrospinal fluid, but none of them are marketed. Examples of some β-secretase inhibitors are LY2886721 (trial ID# NCT01807026 and NCT01561430), E2609 (clinical trial ID# NCT01600859) and MK-8931 (NCT01739348) (Vassar and Kandalepas 2011; Menting and Claassen 2014; Yan and Vassar 2014; Folch et al. 2015).

12.3.2 γ-Secretase Inhibitor The proteolytic enzyme produces Aβ (1–40) and Aβ (1–42) from the membranebound segment C99 of APP. γ-Secretase also has multiple substrates like β-secretase. For example, notch protein, responsible for cell-to-cell communication, proliferation, development and differentiation, is a substrate of γ-secretase (Wolfe 2012).

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Hence, inhibitors of γ-secretase have also contributed to its off-target secondary effects. However, notable example of γ-secretase inhibitors is Semagacestat (LY450139) (Doody et  al. 2013), Avagacestat (Coric et  al. 2012) and selective 𝛾-secretase modulators (SGM) like several nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, sulindac, indomethacin and flurbiprofen (Jaturapatporn et al. 2012). Though Semagacestat is an γ-secretase inhibitor and reduces the load of Aβ in blood and CSF in humans, it has failed severely in the clinical trial (Imbimbo and Giardina 2011).

12.3.3 Cholinesterase Inhibitors AD is associated with loss of cholinergic neurons in the nucleus basalis of Meynert, low cholinergic inputs in the hippocampus and neocortex as well as low release of acetylcholine, reduced muscarinic and nicotinic receptors in the hippocampal and cerebral cortex region of the brain and low release of choline acetyl transferase. However, till now, only two classes of drugs are marketed and approved for the symptomatic treatment of AD, which increase the bioavailability of acetylcholine in synapse. Among these drugs, rivastigmine, donepezil, galantamine and tacrine are acetylcholine esterase inhibitors (AChEI) and N-methyl-D-aspartate (NMDA) receptor antagonist memantine. Unfortunately, none of these drugs are capable of reversing the course of AD nor even slowing down the progression of AD. However, the use of such drugs as combination therapy with other drugs is a trial, and the results are promising. However, different types of synthetic drugs, oligonucleotides, peptides, peptidomimetics, ligands and natural bioactive compounds are reported to be surveyed and systematically analysed for their anti-AD property, but most of them are rejected at the early preliminary stage and few after-phase I/II/III clinical trials (Francis et al. 2005; Folch et al. 2015). Poor bioavailability, inadequate chemical stability in physiological conditions, inability to pass the blood-brain barrier, multiple substrates originated off-target side effects and multifactorial-complex-blurred molecular mechanism of AD are critical limitations for the development of anti-AD therapeutics. Certainly, the application of nanotechnology is one the most powerful tools to surpass the limitations of molecular drugs. Proper nano-formulations of drugs provide enhanced bioavailability as a result of enhanced chemical stability, solubility and permeability. Not merely nano-formulation of conventional drugs but chemically designed anti-AD nanoparticles are also a primary research focus.

12.4 Anti-AD Nanotherapeutics Nanometer length scale compatible with entities of the biological regime, high surface area to volume ratio and chemically tunable surface are the critical attributes for designing nanoparticle-based therapeutics. Due to the size similarity (nanometer

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length scale) with many biological units, nanoparticles can immensely influence various biological processes like protein-protein interaction, nucleotide-protein, receptor-ligand interaction, etc. Depending on the mechanism of action and concept-of-design targeting AD pathological features, nanotherapeutics can be grouped into the following categories: amyloid fibrillation inhibitor, artificial nanochaperone, biomimetics, tau fibrillation inhibitor, oxidative stress modulator and neuroinflammation attenuator. A wide variety of nanoparticles, e.g. polymeric, lipid, noble metal, metal oxide and protein, have been employed to design anti-AD nanoparticles. Biocompatibility, biodegradability, colloidal stability in the complex physiological fluid and metabolism are the major factors for choosing the appropriate nano-system for designing therapeutics towards AD-like neurodegenerative disease (Pradhan et al. 2018).

12.4.1 Anti-amyloid Beta Fibrillation Deposition of extracellular amyloid beta fibrils or plaques is the pathological hallmark of AD progression. Amyloid beta fibrillation is a nucleation-dependent polymerization process, where the polymerization process follows sigmoidal kinetics in nature. It is evident that by virtue of its huge surface free energy along with high surface area, nanoparticles can potently adsorb misfolded protein monomers and oligomers. So, nanoparticles can critically influence the dynamics of protein fibrillation (Fig. 12.1). Size, shape, surface charge, surface functionality, ligand density on the surface of nanoparticles, etc. are a few critical factors to direct its functionality as fibrillation inhibitors or accelerators. Nonspecific adsorption of misfolded protein on nanoparticle surface leads to enhanced local density, which results in faster polymerization. In contrast, specific interactions between surface functionalities, like anti-amyloidogenic molecules, peptides, antibodies, etc., and misfolded monomers arrest the active site for further oligomerization and inhibit further polymerization. A significant amount of research reports has been found in this direction. Table 12.1 summarizes a few important nanoparticles, which inhibit amyloid fibrillation (Jang and Park 2022; Rifaai et al. 2020; Debnath et al. 2017; Pradhan et al. 2017). Various studies have been done to evaluate the mechanistic details and the physicochemical attributes necessary for the proper design of effective amyloid beta fibrillation inhibitor nanoparticles. Few fascinating parameters of nanomodulators are size and curvature, surface charge and hydrophobicity, density and multivalency of anti-amyloidogenic ligands. Cabaleiro-Lago et al. first highlighted that copolymeric nanoparticles (made of NiPAM: BAM; size 40 nm) can retard amyloid beta fibrillation at the nucleation phase efficiently compared to the elongation stage. In addition, polymeric nanoparticle with 100% NiPAM has shown the most effective inhibition property that indicates the degree of surface hydrophilicity and functionalities capable of making hydrogen bonds with misfolded monomer or critical nucleus or oligomers are critical for inhibition of rapid fibrillation process (Cabaleiro-Lago et al. 2008). In recent notable work, Bernd et al. have shown the

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Fig. 12.1  A representative growth curve of amyloid protein fibrillation showing three kinetically distinct phases, i.e. lag phase, elongation and steady state. Nanoparticles can be tuned chemically to interact with amyloid proteins at any phase. Inset TEM images are showing that chemically designed amyloid inhibitor nanoparticles interact with protein or mature fibril. Nanoparticles were added at three phases of growth of amyloid protein, allowed to complete growth followed by the TEM images which were taken. Glutamine-conjugated iron oxide-polymer nanoparticles incubated at the nucleation stage as well as end of lag phase. Trehalose-conjugated iron oxide nanoparticle added prior to the steady state. Small black dots are nanoparticles (indicated by black arrow) are found to bind with protein/fibril (indicated by red arrow) during nucleation/elongation/growth stage. Reproduced with permission (Pradhan et  al. 2018). (Copyright from 2018, Biomacromolecules)

effect of size and surface curvature of nanoparticles on amyloid beta aggregation kinetics. They prepared a small 5 nm size citrated stabilized gold nanoparticle and another large 50  nm citrate-coated gold nanoparticle and studied the interaction with five different small amyloid peptides, including amyloid beta. They found that small-size nanoparticles (5 nm gold nanoparticle) with high surface curvature are potent inhibitors of amyloid beta fibrillation, while the large 50 nm Au nanoparticle is an accelerator of beta fibrillation. Experimental results, along with additional molecular dynamics study, confirmed that the small nanoparticle, due to high surface curvature, destabilizes oligomers significantly, which profoundly inhibits the fibril growth. In contrast, the surface of large nanoparticles with very low curvature

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Table 12.1  List of few novel nanoparticles designed for amyloid fibrillation inhibition Activity/ model used In vitro and ex vivo (4 months old 5XFAD mice brain slice) In vitro and ex-vivo

Synthesis technique Sol-gel coating and calcination

Size/ morphology 33.2 ± 8.2 nm, BFO shell on CFO core

Bismuth oxychloride (BiOCl) nanosheet

Hydrothermal reaction of bismuth (III) nitrate pentahydrate and potassium chloride

Width: 0.8–2.5μm, thickness: 200–470 nm; sheet-like

Nanoquercetin

Nano-emulsion of quercetin

20–30 nm

In vivo AlCl3induced AD rat model

Nanotrehalose

Trehaloseconjugated polyacrylatecoated iron oxide nanoparticle by high temperature colloidal synthesis Low temperature carbonization of trehalose

20–30 nm; spherical

In vitro

106 nm; spherical

In vitro and in vivo; stereotaxic injection followed by red LED irradiation In vitro

Nanoparticle Coppermolybdenum sulphide nanocubes

Mechanism of action NIR-stimulated Aβ fibril dissociation by means of singlet oxygen species (1O2), which were generated by energy transfer from excited electrons in the CMS nanocubes to dissolved oxygen molecules Under red LED irradiation, apta@CDs generate 1O2 to chemically and irreversibly denature Aβ peptides Enhanced BBB permeability and NIR-triggered disaggregation of Aβ fibril

Reference Jang and Park (2021)

Chung et al. (2020)

Liu et al. (2020)

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12.4.3 Biomimetics Conventional nanoparticles use exogenous material as a scaffold, which promotes their early capture by the immune system and further clearance by the liver and kidney, which reduces their bioavailability and therapeutic efficacy considerably. Biomimetic nanoparticles are a novel class of functional nanoparticles which use active monotypic or hybrid biological membranes (Zhao et al. 2021; Yin et al. 2022; Rao 2015) (erythrocyte membrane, lymphocyte membrane, platelet membrane, macrophage membrane, etc.) as ‘shell’ coat or surface coating material on ‘core’ nanoparticles. Due to the presence of intact natural membrane along with their original membrane markers and antigens, it not only nullifies the elimination by the immune system but provides specific interaction with biological targets, allowing prolonged blood circulation, which increases bioavailability as well as the half-life of the encapsulated drug. Undoubtedly, biomimetics offers considerable biocompatibility, biodegradability, blood-brain-barrier penetration properties and low offtarget cytotoxicity before and after degradation. Natural, intact and functional cell membranes are separated from source cells by destroying or lysing cells to empty their intracellular components. Cell membranes can be separated from blood or tissues by ultrasound (Rao 2015) freeze-thaw (Amini et  al. 2020), extrusion (Insua et al. 2016), hypotonicity (Gao et al. 2020a, b), etc. For example, Gao et al. synthesized red-blood-cell membrane camouflaged human serum albumin nanoparticles for the successful delivery of natural antioxidant curcumin to the neuronal mitochondria of the AD brain (Fig. 12.5). This core-shell-like engineered biomimetic nanoparticle has an HSA core and RBC membrane as the shell. The emulsification ultrasonication method was used for core HSA np formation, whereas hypotonic treatment methods were used for RBC membrane separation from ICR mice blood cells. The hydrophobic core encapsulates curcumin. To enhance the targeting efficiency, the surface of the membrane was functionalized with mitochondria targeting ligand triphenyl phosphonium ion (TPP), and T807, 7-(6-nitropyridin-3-yl)5H-pyrido[4,3-b] indole, is a positron emission tomography (PET) imaging agent that can quickly cross the BBB and specifically bind to nerve cells in the form of functional conjugates DSPE-PEG3400-T807 or DSPE-PEG2000-TPP via lipid insertion method (Kwon et al. 2016). Finally, these two components (HAS np and ligandmodified RBC membrane) were fused under the mechanical force via the physical extrusion method to prepare an RBC membrane-coated HSA nanoparticle. The dual-ligand-modified biomimetic nanoparticle CUR-loaded T807/TPP-RBC-NPs have shown multifaceted activity. The treated mice showed improved spatial learning ability tested by the MWM experiment and cognitive ability in AD model mice compared with that of other groups. In addition, it significantly improved the neuronal survival in the CA1 region of the hippocampus of AD mouse model by reducing the ROS level via modulation of brain SOD activity and the level of H2O2, γ-GT and MDA. Furthermore, it could mitigate the neuroinflammation in the brain by reducing the mitochondrial ROS levels confirmed by reduced levels of Iba1 and GFAP immunoreactivities (Gao et al. 2020a, b). Table 12.3 highlights some notable examples of reported anti-amyloid biomimetic nanoparticles (Gao et al. 2020a, b; Song et al. 2014; Han et al. 2020, 2021).

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Fig. 12.5 (a) The synthesis of scheme of T807/TPP-RBC-NPs. Initially, the RBC membrane is derived from RBCs, and NPs without functionalization are prepared using an emulsification ultrasonication method. Next, the bare NPs’ surface is coated by derived RBC membranes through mechanical extrusion, and finally RBC-NPs is formed. After that, DSPE-PEG3400-T807/DSPEPEG2000-TPP are inserted into the outer monolayer of RBC membranes to form T807/TPP-RBCNPs. (b) Representative SDS-PAGE protein analysis of RBC membranes with various biomimetic formulations. (c) TEM image shows the morphological appearance of T807/TPP-RBC-NPs. (Reproduced with permission Gao et al. (2020a, b). Copyright from 2020 Acta Biomaterialia)

12.4.4 Tau Modulator Nanoparticle Deposition of intracellular neurofibrillary tangles (NFT), primarily composed of hyperphosphorylated tau protein is another significant pathological feature of AD. Inhibition of tau hyperphosphorylation and degradation of tau aggregates are two targets for AD therapeutics development. Tau is a microtubule-associated protein found majorly in axons of healthy neurons of the central nervous system and peripheral nervous system. In general, the tau protein is responsible for providing stability to microtubules and regulating the intracellular trafficking. During the AD progression, post-translational hyperphosphorylation of tau promotes abnormal

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Table 12.3  List of a few notable designed biomimetic nanoparticles for amyloid fibrillation inhibition Biomimetic nanoparticle Model used In vivo

Nanomodulator RBC membranecoated curcuminloaded HSA NP modified with TPP and T807 T807/RPCNPCUR NPs

Activity Reduced hippocampal mitochondrial dysfunction in AD

Structural components RBC membrane-coated HSA NP, curcumin

Inhibit tau aggregation

In vivo

Gao et al. (2020a, b)

ApoE3-rHDL nanodisc 27.9 ± 8.9

Improve microglial and astroglial degradation of Aβ, reduce amyloid deposition and rescue memory deficit of SAMP8 mice Penetrate BBB, attenuate Aβ-related mitochondrial stress and improve memory impairment in APP/PS1 mice

RBC membrane-coated HSA NP, curcumin, DSPE-PEG3400-T807 DMPC, synthetic recombinant ApoE3

In vivo and in vitro

Song et al. (2014)

Resveratrol encapsulated RBC membrane-coated nanostructured lipid carriers (NLC) bearing rabies virus glycoprotein (RVG29) and triphenylphosphine cation (TPP) molecule Genistein encapsulated macrophage membranecoated solid lipid nanoparticle bearing RVG29 and TPP

In vivo and in vitro

Han et al. (2020)

In vitro

Han et al. (2021)

RVG/TPP NPs@ RBCm

RVG/ TPPMASLNs-GS

Mitigate neuronal mitochondrial oxidative stress

Reference Gao et al. (2020a, b)

sequestration in the soma and nucleus of neurons, which hampers its normal function by reducing the affinity for microtubule and tubulin and finally form neurofibrillary tangles. Several nanomaterials have shown potent tau aggregation inhibition properties. For example, Gao C. et al. designed a tau-targeting biomimetic nanoparticle, a curcumin-loaded T807-functionalized red-blood-cell membrane-coated PLGA nanoparticle (Fig. 12.6). The CUR-loaded T807/RPCNP NPs can alleviate AD symptoms in OA-treated AD model mice by decreasing p-tau levels and reducing neuronal-like cell death (Fig. 12.7) both in vitro and in vivo (Gao et al. 2020a, b). The memory impairment of the AD mouse model is significantly improved following systemic administration of CUR-loaded T807/RPCNP NPs (Fig. 12.8).

Fig. 12.6 (a) Identification of neuronal survival in the hippocampal CA1 region of AD model mice after i.v. injection of with different CUR-loaded formulations. Normal pyramidal neurons shows round and pale nuclei, while dying or dead neurons exhibit pyknotic nuclei, condensed cytoplasm or enhanced eosinophilic staining. All photomicrographs are 100× and 400× (n = 5). (b) Changes in the SOD, γ - GT, MDA and H2O2 levels in the hippocampal area of AD model mice after i.v. injection of with different CUR-loaded formulations. The data are presented as the means ± SD (n = 5). * indicates P < 0.05. ** indicates P < 0.01. (Reproduced with permission Gao et al. (2020a, b). Copyright from 2020 Acta Biomaterialia)

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12.4.5 Neuroinflammation Modulator Nanoparticle Increasing evidence suggests that AD pathogenesis is associated with chronic neuroinflammation, release of proinflammatory cytokines (IL-1β, TNFα, IL-6) and activation of phagocytic microglia, along with reactivated astrocytes, which are anticipated to be initiated and modulated by multiple inflammation-related pathways, such as the NF-κB pathway (Akama et al. 1998), the JAK/STAT3 pathway (Ben Haim et al. 2015), MAPK pathway (Agusti et al. 2011) and the calcineurin pathway (Furman and Norris 2014; Sompol et  al. 2017). Furthermore, activation and higher expression of inflammasomes like NLRP3 have been found in AD, which further promotes the aggregation and hyperphosphorylation of tau protein also. The development of pharmacological ingredients targeting inflammatory pathways, microglia, astrocytes and inflammasomes is an emerging avenue for anti-AD

Fig. 12.7 (a) Schematic interpretation of T807/RPCNP-CUR in  vivo. The precise targeting of T807, a novel engineered biomimetic delivery nanosystems store in neurons after crossing the BBB. (b) The preparation scheme of T807/RPCNP-CUR.  First, the RBC membrane is derived from RBCs, and nonfunctionalized NPs are prepared by emulsification ultrasonication method. Next, the surface of bare NPs is coated by the derived RBC membranes through mechanical extrusion to form RPCNP-CUR. Finally, DSPE-PEG3400-T807 is inserted into the outer monolayer of RBC membrane to form T807/RPCNP-CUR NPs. (c) TEM image showing the morphological appearance of RBC, PCNP-CUR, RPCNP-CUR and T807/RPCNP-CUR. (Reproduced with permission Gao et al. (2020a, b). Copyright from 2020 Journal of Nanobiotechnology)

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Fig. 12.8  Therapeutic effect of CUR-loaded biomimetic formulations in vitro. (a) p-tau Elisa kit analysis of cellular total p-tau level after treated with different formulations in OA-treated HT22 cells. (b) Western blot and (c) quantification results for hyperphosphorylated tau at threonine 205 epitopes, serine 396 and 404 epitopes in HT22 cells. Statistical analysis was performed using a one-way ANOVA test, with *** indicating p. (Reproduced with permission Gao et al. (2020a, b). Copyright from 2020 Journal of Nanobiotechnology)

drug research. Nanotherapeutics, which can modulate neuroinflammation, is therefore a prime research focus. Various designed nano modulators are reported, which can significantly influence neuroinflammation in AD mouse models. For example, Zhang et al. prepared an Aβ cleaner nanoparticle (Fig. 12.9), which can normalize the polarization of dysfunctional microglia, reduce the burden of Aβ deposits and shift its degradation pathway of from lysosomal to proteasomal (Liu et  al. 2019). The mannose (Man) terminated di-block copolymer of zwitterionic poly(carboxy betaine) (PCB) and the positively charged ROS-responsive polymer poly[(2-acryloyl) ethyl (p-boronic acid benzyl) dimethylammonium bromide] (PB). The di-block copolymer was self-assembled via hydrophobic interaction to form a nanoparticle. The fingolimod and ZnO were encapsulated into the hydrophobic region of the Man-PCB-PB nanoparticle (MCPZF). Furthermore, the siSTAT3 was condensed with the positively charged MCPZF to form an MCPZFS nanoparticle. The PCB was chosen for endosomal/lysosomal escape, and better cellular uptake compared to polyethylene glycol and PB used for siSTAT3 condensation and ROSresponsive release. The proposed mechanism of action of MCPZFS nanoparticle is to penetrate BBB and endocytose in microglia via mannose receptor, where nanoparticles would immediately come out to the cytosol due to subsequent endosomal escape (Fig. 12.10). In the cytosol, the nanoparticles were broken up due to elevated

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Fig. 12.9  Evaluation of in vivo therapeutic effect of CUR-loaded biomimetic formulations. (a) Mean velocity of mice in different formulation groups. (b) Escape latency time of each group. (c) The frequency of crossing platform at the final day with the platform removed. (d) Relative time spent on the target quadrant. (e) Representative swimming path tracings of mice in different groups. The data are presented as the mean ± SD (n = 20). * indicates p